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Hosseini F, Ahmadi A, Sarvi ZN, Iranshahi M, Rassouli FB. 7-Geranyloxycoumarin modulated metastatic potential of osteosarcoma cells via interaction with MMPs and JAK1/2. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03847-z. [PMID: 39954065 DOI: 10.1007/s00210-025-03847-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 01/23/2025] [Indexed: 02/17/2025]
Abstract
Osteosarcoma (OS) is a highly aggressive bone cancer that primarily affects young adults. The tumor microenvironment and molecular mediators, including Janus kinases (JAKs) and matrix metalloproteinases (MMPs), significantly influence OS metastasis; activation of the JAK/STAT pathway enhances MMP expression and activity, promoting OS metastasis. 7-Geranyloxycoumarin, a natural agent found in various edible fruits and vegetables, possesses valuable pharmaceutical activities. This study aimed to investigate the effects of 7-geranyloxycoumarin on the metastasis of OS cells for the first time. To achieve this, a protein-protein interaction (PPI) network was constructed from the potential molecular and pathogenic targets associated with 7-geranyloxycoumarin and OS to identify overlapping targets. Subsequently, GO and KEGG pathway enrichment analyses were conducted. Molecular docking and dynamic simulations were also performed to elucidate the binding affinity of 7-geranyloxycoumarin with JAK1 and JAK2. For in vitro studies, 7-geranyloxycoumarin was first extracted from Ferula szowitsiana using thin-layer chromatography. The cells were then treated and evaluated for viability, apoptosis, migration, invasion, adhesion, and MMPs activity. The study identified 50 shared targets and revealed MMP-2, MMP-9, JAK1, and JAK2 as hub genes, confirmed through enrichment analyses. Molecular docking revealed strong interactions between 7-geranyloxycoumarin and JAK1 and JAK2 proteins, and molecular dynamics simulations indicated both conformational flexibility and binding stability of the ligand-protein complex. Moreover, experimental studies demonstrated that 7-geranyloxycoumarin did not induce apoptosis but significantly altered the migration, invasion, and adhesion of OS cells by inhibiting the activity of MMPs. In conclusion, 7-geranyloxycoumarin is proposed as a promising therapeutic agent for targeting metastasis in OS cells.
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Affiliation(s)
- Fatemehsadat Hosseini
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Abdolreza Ahmadi
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Zahra Nasiri Sarvi
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mehrdad Iranshahi
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh B Rassouli
- Novel Diagnostics and Therapeutics Research Group, Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran.
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Wang X, Wang J, Wang L, Song M, Meng H, Guo E, Miao S. CTSL Promotes Autophagy in Laryngeal Cancer Through the IL6-JAK-STAT3 Signalling Pathway. J Cell Mol Med 2025; 29:e70364. [PMID: 39893643 PMCID: PMC11787816 DOI: 10.1111/jcmm.70364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 12/24/2024] [Accepted: 01/06/2025] [Indexed: 02/04/2025] Open
Abstract
Cathepsin L (CTSL) is an important oncogene. However, its mechanism of action in laryngeal cancer is still unclear. This study aims to explore the role of CTSL in laryngeal cancer and its clinical significance. Conducting bioinformatics analysis utilising the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Performing CCK8 analysis, Western blotting, qRT-PCR, wound healing assay and transwell invasion assay. Additionally, conducting immunoprecipitation experiments and immunohistochemical staining to investigate the impact of CTSL on cell proliferation, autophagy and related signalling pathways. We observed a significant upregulation of CTSL in laryngeal cancer tissues, and its elevated levels are indicative of poor prognosis in laryngeal cancer patients. The proliferation of laryngeal cancer cells relies on the expression of CTSL, with overexpression of this gene enhancing the proliferative capacity of these cells. Concurrently, CTSL is closely associated with the autophagic levels in laryngeal cancer cells. During the autophagic process mediated by CTSL, the IL6-JAK-STAT3 signalling pathway is activated, suggesting that CTSL promotes autophagy through the IL6-JAK-STAT3 pathway. Considering the correlation between CTSL and autophagy, we developed and validated a multi-gene signature. The risk score derived from this signature demonstrates significant potential in predicting various aspects. We found that CTSL upregulates autophagy in laryngeal cancer cells by activating the IL6-JAK-STAT3 signalling pathway. By taking into account the autophagy-regulating role of CTSL, the clinical predictive ability of CTSL in HNSC can be enhanced.
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Affiliation(s)
- Xueying Wang
- Department of Otolaryngology Head and Neck SurgeryXiangya Hospital, Central, South UniversityChangshaHunanChina
- Otolaryngology Major Disease Research Key Laboratory of Hunan ProvinceChangshaHunanChina
- Clinical Research Center for Laryngopharyngeal and Voice Disorders in Hunan, ProvinceChangshaHunanChina
| | - Junrong Wang
- Department of Otorhinolaryngology Head and Neck SurgeryHarbin Medical, University Cancer HospitalHarbinHeilongjiangChina
| | - Lei Wang
- Department of Otorhinolaryngology Head and Neck SurgeryHarbin Medical, University Cancer HospitalHarbinHeilongjiangChina
| | - Ming Song
- Department of Otorhinolaryngology Head and Neck SurgeryHarbin Medical, University Cancer HospitalHarbinHeilongjiangChina
| | - Hongxue Meng
- Department of PathologyHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Erliang Guo
- Department of Thoracic SurgeryHarbin Medical University Cancer HospitalHarbinHeilongjiangChina
| | - Susheng Miao
- Department of Otorhinolaryngology Head and Neck SurgeryHarbin Medical, University Cancer HospitalHarbinHeilongjiangChina
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Chen S, Wei P, Wang G, Wu F, Zou J. Construction of a prognostic signature based on T-helper 17 cells differentiation-related genes for predicting survival and tumor microenvironment in head and neck squamous cell carcinoma. Medicine (Baltimore) 2025; 104:e41273. [PMID: 39854737 PMCID: PMC11771614 DOI: 10.1097/md.0000000000041273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/16/2024] [Accepted: 01/02/2025] [Indexed: 01/26/2025] Open
Abstract
T-helper 17 (Th17) cells significantly influence the onset and advancement of malignancies. This study endeavor focused on delineating molecular classifications and developing a prognostic signature grounded in Th17 cell differentiation-related genes (TCDRGs) using machine learning algorithms in head and neck squamous cell carcinoma (HNSCC). A consensus clustering approach was applied to The Cancer Genome Atlas-HNSCC cohort based on TCDRGs, followed by an examination of differential gene expression using the limma package. Machine learning techniques were utilized for feature selection and model construction, with validation performed using the GSE41613 cohort. The interplay between the predictive marker, immune landscape, immunotherapy response, drug sensitivity, and clinical outcomes was assessed, and a nomogram was constructed. Functional evaluations of TCDRGs were conducted through colony formation, transwell invasion, and wound healing assays. Two distinct HNSCC subtypes with significant differences in prognosis were identified based on 87 TCDRGs, indicating different levels of Th17 cell differentiation. Thirteen differentially expressed TCDRGs were selected and used to create a risk signature, T17I, using the random survival forest algorithm. This signature was associated with grade, chemotherapy, radiotherapy, T stage, and somatic mutations. It was revealed that there were differences in the immune response-related pathways between the high- and low-risk groups. Inflammatory pathways were significantly activated in the low-risk group. The T17I signature was associated with immune infiltration. Specifically, there was a higher infiltration of immune activation cells in the low-risk group, whereas the high-risk group had a higher infiltration of M2 macrophages. In addition, the T17I signature was significantly associated with drug sensitivity. A nomogram combining age, radiotherapy, and the T17I signature accurately predicted the prognosis of patients with HNSCC. Finally, in vitro experiments confirmed that knockdown of LAT gene expression promotes proliferation, metastasis, and invasion of HNSCC cells. In conclusion, this study successfully identified molecular subtypes and constructed a prognostic signature and nomogram based on TCDRGs in HNSCC, which may aid in personalized treatment strategies.
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Affiliation(s)
- Shiqin Chen
- Department of Otorhinolaryngology and Head and Neck Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, Anhui, China
| | - Pingcun Wei
- Department of Otorhinolaryngology and Head and Neck Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, Anhui, China
| | - Gang Wang
- Department of Otorhinolaryngology and Head and Neck Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, Anhui, China
| | - Fan Wu
- Department of Otorhinolaryngology and Head and Neck Surgery, Anhui No.2 Provincial People’s Hospital, Hefei, Anhui, China
| | - Jianjun Zou
- Department of Otolaryngology, Hangzhou Red Cross Hospital (Zhejiang Hospital of Integrated Traditional Chinese and Western Medicine), Hangzhou, Zhejiang, China
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Bărăian AI, Raduly L, Zănoagă O, Iacob BC, Barbu-Tudoran L, Dinte E, Berindan-Neagoe I, Bodoki E. Targeting JAK/STAT3 in glioblastoma cells using an alginate-PNIPAm molecularly imprinted hydrogel for the sustained release of ruxolitinib. Int J Biol Macromol 2025; 298:140025. [PMID: 39828178 DOI: 10.1016/j.ijbiomac.2025.140025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/19/2024] [Accepted: 01/16/2025] [Indexed: 01/22/2025]
Abstract
Glioblastoma (GBM) is a notoriously aggressive primary brain tumor characterized by elevated recurrence rates and poor overall survival despite multimodal treatment. Local treatment strategies for GBM are safer and more effective alternatives to systemic chemotherapy, directly tackling residual cancer cells in the resection cavity by circumventing the blood-brain barrier. Molecularly imprinted polymers (MIPs) are promising drug delivery systems due to their high-affinity binding cavities that enable tailored release kinetics. This study reports the development of a semi-synthetic polysaccharide MIP-based hydrogel intended for the post-surgical management of GBM. The biodegradable implant, made of calcium-crosslinked alginate-poly(N-isopropylacrylamide) graft copolymer, was designed for the sustained release of ruxolitinib (RUX) in the resection cavity, targeting the Janus kinase/Signal Transducer and Activator of Transcription-3 signaling pathway. The molecularly imprinted hydrogel demonstrated thermo-thickening and shear-thinning behavior, high entrapment efficiency of RUX (84.59 ± 0.73 %), and sustained release over 14 days, underscoring the advantages that molecular imprinting of the alginate matrix provides compared to conventional MIPs. The dose-dependent inhibitory effects of the imprinted hydrogel against U251 and A172 GBM cells were demonstrated by increased apoptosis, reduced confluence, colony formation, and delayed wound healing, whereas the non-imprinted hydrogel was biocompatible. The MIP hydrogel could be a safe and effective GBM treatment.
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Affiliation(s)
- Alexandra-Iulia Bărăian
- Department of Analytical Chemistry and Instrumental Analysis, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Lajos Raduly
- Research Centre for Functional Genomics, Biomedicine, and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Oana Zănoagă
- Research Centre for Functional Genomics, Biomedicine, and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Bogdan-Cezar Iacob
- Department of Analytical Chemistry and Instrumental Analysis, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | | | - Elena Dinte
- Department of Pharmaceutical Technology and Biopharmaceutics, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Centre for Functional Genomics, Biomedicine, and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ede Bodoki
- Department of Analytical Chemistry and Instrumental Analysis, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania.
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5
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Mariana SM, Brenda RP, Heriberto PG, Cristina L, David B, Guadalupe ÁL. GPER1 activation by estrogenic compounds in the inflammatory profile of breast cancer cells. J Steroid Biochem Mol Biol 2025; 245:106639. [PMID: 39571822 DOI: 10.1016/j.jsbmb.2024.106639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/28/2024] [Accepted: 11/19/2024] [Indexed: 11/24/2024]
Abstract
Breast cancer (BC) is the most frequent female neoplasm worldwide. Its establishment and development have been related to inflammatory cytokine expression. Steroid hormones such as estradiol (E2) can regulate proinflammatory cytokine secretion through interaction with its nuclear receptors. However, little is known regarding the activation of its membrane estrogen receptor (GPER1) and the inflammatory cytokine environment in BC. We have studied the synthesis and biological effects of molecules analogs to E2 for hormone replacement therapy (HRT), such as pentolame. Nevertheless, its interaction with GPER1 and the modulation of inflammatory cytokines in different BC types has been barely studied and deserves deeper investigation. In this research, the role of GPER1 in the proliferation and modulation of inflammatory cytokines involved in carcinogenesis and metastatic processes in different BC cell lines was assessed by binding to various compounds. To achieve this goal, the presence of GPER1 was identified in different BC cell lines. Subsequently, cell proliferation after exposure to E2, pentolame and GPER1 agonist, G1, was subsequently determined alone or in combination with the GPER1 antagonist, G15. Finally, the pro-inflammatory cytokine secretion derived from the supernatants of BC cells exposed to the previous treatments was also assessed. Interestingly, GPER1 activation or inhibition has significant effects on the cytokine regulation associated with invasion in BC. Notably, pentolame did not induce cell proliferation or increase the proinflammatory cytokine expression compared to E2 in BC cell lines. In addition, pentolame did not induce the presence of the cell adhesion molecule PECAM-1. In contrast, E2 treatment weakly induced the expression of PECAM-1 in MCF-7 and HCC1937 cells, and G1 treatment showed this effect only in MCF-7 cells. The results suggest that GPER1 might be a significant inflammatory modulator with angiogenic-related effects in BC cells. In addition, pentolame might represent an HRT alternative in patients with BC predisposition.
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Affiliation(s)
- Segovia-Mendoza Mariana
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
| | - Reyes-Plata Brenda
- Facultad de Estudios Superiores Zaragoza. Universidad Nacional Autónoma de México,Ciudad de México, Mexico
| | - Prado-Garcia Heriberto
- Laboratorio de Onco-Inmunobiología, Departamento de Enfermedades Crónico-Degenerativas, Instituto Nacional de Enfermedades Respiratorias, "Ismael Cosio Villegas" Calzada de Tlalpan 4502, Col. Sección XVI, Ciudad de México 14080, Mexico
| | - Lemini Cristina
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Barrera David
- Departamento de Biología de la Reproducción "Dr. Carlos Gual Castro", Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Belisario Domínguez, Sección XVI, Ciudad de México 14080, Mexico
| | - Ángeles-López Guadalupe
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad de México, Mexico.
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6
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Agnoletto A, Brisken C. Hormone Signaling in Breast Development and Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:279-307. [PMID: 39821031 DOI: 10.1007/978-3-031-70875-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Hormones control normal breast development and function. They also impinge on breast cancer (BC) development and disease progression in direct and indirect ways. The major ovarian hormones, estrogens and progesterone, have long been established as key regulators of mammary gland development in rodents and linked to human disease. However, their roles have been difficult to disentangle because they act on multiple tissues and can act directly and indirectly on different cell types in the breast, and their receptors interact at different levels within the target cell. Estrogens are well-recognized drivers of estrogen receptor-positive (ER+) breast cancers, and the ER is successfully targeted in ER+ disease. The role of progesterone receptor (PR) as a potential target to be activated or inhibited is debated, and androgen receptor (AR) signaling has emerged as a potentially interesting pathway to target on the stage.In this chapter, we discuss hormone signaling in normal breast development and in cancer, with a specific focus on the key sex hormones: estrogen, progesterone, and testosterone. We will highlight the complexities of endocrine control mechanisms at the organismal, tissue, cellular, and molecular levels. As we delve into the mechanisms of action of hormone receptors, their interplay and their context-dependent roles in breast cancer will be discussed. Drawing insights from new preclinical models, we will describe the lessons learned and the current challenges in understanding hormone action in breast cancer.
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Affiliation(s)
- Andrea Agnoletto
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
| | - Cathrin Brisken
- Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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7
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Chen Y, Ouyang W, Lv H, Chen W. Exploring the mechanisms by which common inhalational anesthetics influence malignant tumor metastasis: A data mining study based on comparative toxicogenomic databases. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2025; 289:117660. [PMID: 39765114 DOI: 10.1016/j.ecoenv.2024.117660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/26/2025]
Abstract
Surgery remains the primary treatment for solid malignant tumors, but controlling postoperative tumor recurrence and metastasis continues to be a major challenge. Understanding the factors that influence tumor recurrence and metastasis after surgery, as well as the underlying biological mechanisms, is critical. Previous studies suggest that anesthetic agents may increase the risk of tumor recurrence and metastasis in patients with cancer, but the mechanisms underlying these findings remain unclear. In this study, we utilized toxicogenomics and comparative toxicogenomic databases to analyze data and explore the potential mechanisms by which three commonly used inhalational anesthetics-sevoflurane, isoflurane, and halothane-might promote malignant tumor metastasis. The results identified 18 genes that may be associated with tumor metastasis. Functional enrichment analysis revealed that these anesthetics could influence tumor cell migration by activating signaling pathways such as the IL-17 and tumor necrosis factor signaling pathways, thereby potentially inducing tumor metastasis. Moreover, by constructing a TF-mRNA network, we predicted several transcription factors that might play key roles in anesthetic-induced tumor metastasis. The analysis revealed a total of 87 regulatory relationships between transcription factors and mRNA. These findings offer new insights for future in vivo or in vitro studies and contribute to a better understanding of the relationship between inhalational anesthetics and tumor metastasis, providing valuable reference points for clinical decision-making. The results of this study also provide a reference for the determination of subsequent clinical treatment targets. Hence, future laboratory studies should prioritize investigating the specific genes and common mechanisms identified in this study.
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Affiliation(s)
- Yiyu Chen
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wenlan Ouyang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Hu Lv
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Wei Chen
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai 200032, China.
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8
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Zuo Q, Kang Y. Metabolic Reprogramming and Adaption in Breast Cancer Progression and Metastasis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2025; 1464:347-370. [PMID: 39821033 DOI: 10.1007/978-3-031-70875-6_17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2025]
Abstract
Recent evidence has revealed that cancer is not solely driven by genetic abnormalities but also by significant metabolic dysregulation. Cancer cells exhibit altered metabolic demands and rewiring of cellular metabolism to sustain their malignant characteristics. Metabolic reprogramming has emerged as a hallmark of cancer, playing a complex role in breast cancer initiation, progression, and metastasis. The different molecular subtypes of breast cancer exhibit distinct metabolic genotypes and phenotypes, offering opportunities for subtype-specific therapeutic approaches. Cancer-associated metabolic phenotypes encompass dysregulated nutrient uptake, opportunistic nutrient acquisition strategies, altered utilization of glycolysis and TCA cycle intermediates, increased nitrogen demand, metabolite-driven gene regulation, and metabolic interactions with the microenvironment. The tumor microenvironment, consisting of stromal cells, immune cells, blood vessels, and extracellular matrix components, influences metabolic adaptations through modulating nutrient availability, oxygen levels, and signaling pathways. Metastasis, the process of cancer spread, involves intricate steps that present unique metabolic challenges at each stage. Successful metastasis requires cancer cells to navigate varying nutrient and oxygen availability, endure oxidative stress, and adapt their metabolic processes accordingly. The metabolic reprogramming observed in breast cancer is regulated by oncogenes, tumor suppressor genes, and signaling pathways that integrate cellular signaling with metabolic processes. Understanding the metabolic adaptations associated with metastasis holds promise for identifying therapeutic targets to disrupt the metastatic process and improve patient outcomes. This chapter explores the metabolic alterations linked to breast cancer metastasis and highlights the potential for targeted interventions in this context.
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Affiliation(s)
- Qianying Zuo
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, USA
| | - Yibin Kang
- Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
- Ludwig Institute for Cancer Research Princeton Branch, Princeton, NJ, USA.
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9
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Li T, Song X, Chen J, Li Y, Lin J, Li P, Yu S, Durojaye OA, Yang F, Liu X, Li J, Cheng S, Yao X, Ding X. Kupffer Cell-derived IL6 Promotes Hepatocellular Carcinoma Metastasis Via the JAK1-ACAP4 Pathway. Int J Biol Sci 2025; 21:285-305. [PMID: 39744421 PMCID: PMC11667824 DOI: 10.7150/ijbs.97109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Accepted: 11/22/2024] [Indexed: 01/21/2025] Open
Abstract
Tumor-associated macrophages (TAMs), which differentiate from tissue-resident macrophages, are recognized for their ability to influence cancer progression and metastasis. However, the specific role of Kupffer cells (KCs), the intrinsic macrophages of the liver, in the progression of hepatocellular carcinoma (HCC) remains unclear. In this study, we describe a novel mechanism by which exosomes derived from HCC cells induce KCs to transition into TAMs, thereby facilitating the metastasis of HCC in an IL6-JAK1-ACAP4 axis-dependent manner. Mechanistically, the exosome-mediated domestication of KCs by hepatoma cells constitutes one of the primary sources of IL6 production in the HCC microenvironment. IL6 then activates JAK1 to phosphorylate its downstream effector ACAP4 at Tyr843, a novel phosphorylation site identified in this context, which in turn promotes ARF6-GTPase activity and hepatoma cell migration. Furthermore, we found that the levels of IL6, as well as the phosphorylation of JAK1 and ACAP4 at Tyr843, were significantly greater in tumor tissues from HCC patients than in adjacent tissues. These findings suggest that the IL6-JAK1-ACAP4 axis may be a promising therapeutic target for HCC. Importantly, we screened bufalin, an active ingredient derived from Venenum Bufonis, and discovered that it inhibits JAK1 and disrupts the IL6-induced phosphorylation of ACAP4. This inhibition not only impairs hepatoma cell migration but also prevents the metastasis of HCC. These findings demonstrate the interplay between hepatoma cells and KCs through the IL6-JAK1-ACAP4 axis, thereby promoting HCC metastasis, and reveal the therapeutic potential of bufalin for the treatment of HCC through JAK1 inhibition.
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Affiliation(s)
- Tao Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xiaoyu Song
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China
| | - Jiena Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Yuan Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of Traditional Chinese Medicine Constitution and Preventive Treatment of Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jie Lin
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of Traditional Chinese Medicine Constitution and Preventive Treatment of Diseases, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ping Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
| | - Simiao Yu
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
- Department of Hepatobiliary, The Fifth Medical Center of PLA General Hospital, Beijing, 100039, China
| | - Olanrewaju Ayodeji Durojaye
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China
| | - Fengrui Yang
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China
| | - Xing Liu
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China
| | - Jian Li
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Shiyuan Cheng
- Department of Neurology, Northwestern Malnati Brain Tumor Institute, The Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Xuebiao Yao
- MOE Key Laboratory of Membraneless Organelle and Cellular Dynamics, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027, China
| | - Xia Ding
- School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China
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10
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Liu S, Qiu F, Gu R, Xu E. Functional Involvement of Signal Transducers and Activators of Transcription in the Pathogenesis of Influenza A Virus. Int J Mol Sci 2024; 25:13589. [PMID: 39769350 PMCID: PMC11677356 DOI: 10.3390/ijms252413589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/14/2024] [Accepted: 12/17/2024] [Indexed: 01/11/2025] Open
Abstract
Signal transducers and activators of transcription (STATs) function both as signal transducers and transcription regulators. STAT proteins are involved in the signaling pathways of cytokines and growth factors; thus, they participate in various life activities and play especially critical roles in antiviral immunity. Convincing evidence suggests that STATs can establish innate immune status through multiple mechanisms, efficiently eliminating pathogens. STAT1 and STAT2 can activate the antiviral status by regulating the interferon (IFN) signal. In turn, suppressor of cytokine signaling-1 (SOCS1) and SOCS3 can modulate the activation of STATs and suppress the excessive antiviral immune response. STAT3 not only regulates the IFN signal, but also transduces Interleukin-6 (IL-6) to stimulate the host antiviral response. The function of STAT4 and STAT5 is related to CD4+ T helper (Th) cells, and the specific mechanism of STAT5 remains to be studied. STAT6 mainly exerts antiviral effects by mediating IL-4 and IL-13 signaling. Here, we reviewed the recent findings regarding the critical roles of STATs in the interactions between the host and viral infection, especially influenza A virus (IAV) infection. We also discuss the molecular mechanisms underlying their functions in antiviral responses.
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Affiliation(s)
- Shasha Liu
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Feng Qiu
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Rongrong Gu
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Erying Xu
- Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
- Joint Laboratory of Animal Pathogen Prevention and Control of Fujian-Nepal, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
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11
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Wang Y, Zhong P, Wang C, Huang W, Yang H. Genetic overlap between breast cancer and sarcopenia: exploring the prognostic implications of SLC38A1 gene expression. BMC Cancer 2024; 24:1533. [PMID: 39695419 DOI: 10.1186/s12885-024-13326-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 12/10/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Sarcopenia, an age-related syndrome characterized by a decline in muscle mass, not only affects patients' quality of life but may also increase the risk of breast cancer recurrence and reduce survival rates. Therefore, investigating the genetic mechanisms shared between breast cancer and sarcopenia is significant for the prevention, diagnosis, and treatment of breast cancer. METHODS This study downloaded gene expression datasets and clinical data related to breast cancer and skeletal muscle aging from the GEO database. Data preprocessing, integration, differential gene identification, functional enrichment analysis, and construction of protein-protein interaction networks were performed using R language. Subsequently, COX proportional hazards model analysis and survival analysis were conducted, and survival curves and nomograms were generated. The expression levels of genes in tissues were detected using qRT-PCR, and the Radiant DICOM viewer software was used to delineate the pectoralis major muscle area in CT images. RESULTS We identified 152 differentially expressed genes (P < .05) and 226 sarcopenia-related genes (r > .4) associated with skeletal muscle aging. The TCGA-BRCA dataset revealed 106 genes associated with breast cancer (P < .05, logFC = 1). Functional enrichment analysis indicated significant enrichment in cell proliferation and growth pathways. The PPI network identified critical molecules involved in muscle aging and tumor progression. After dimensionality reduction, a strong correlation was observed between the expression of the muscle aging-related gene set and the prognosis of breast cancer patients (P < .01). The expression of SLC38A1 identified through multivariate COX analysis was significantly associated with poor prognosis in breast cancer patients (P = .03). Incorporating SLC38A1 expression, the prognostic model precisely forecasted breast cancer survival (P < .01). External validation confirmed the higher expression of the SLC38A1 gene in breast cancer tissues compared to adjacent non-cancerous tissues (P < .01). The SLC38A1 index, calculated in combination with the patient's age and BMI, can optimize the prognostic prediction model, providing a powerful tool for personalized treatment of breast cancer. CONCLUSION High SLC38A1 gene expression was significantly associated with poor prognosis in breast cancer patients. The combination of SLC38A1 expression and the pectoralis major muscle area provided an optimized prognostic prediction model, offering a potential tool for personalized breast cancer treatment.
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Affiliation(s)
- Ye Wang
- Internet Hospital Operation Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Pei Zhong
- First clinical college of medicine, Guangxi Medical University, Nanning, China
| | - Congjun Wang
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Weijia Huang
- Guangxi Zhuang Autonomous Region Engineering Research Center for Artificial Intelligence Analysis of Multimodal Tumor Images, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hong Yang
- Department of Medical Ultrasound, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, China.
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12
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Zha Z, Ge F, Li N, Zhang S, Wang C, Gong F, Miao J, Chen W. Effects of Na V1.5 and Rac1 on the Epithelial-Mesenchymal Transition in Breast Cancer. Cell Biochem Biophys 2024:10.1007/s12013-024-01625-x. [PMID: 39673684 DOI: 10.1007/s12013-024-01625-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2024] [Indexed: 12/16/2024]
Abstract
Breast cancer is a disease that seriously endangers the health of women. However, it is difficult to treat due to the emergence of metastasis and drug resistance. Exploring the metastasis mechanism of breast cancer is helpful to aim for the appropriate target. The epithelial-mesenchymal transition (EMT) is an important mechanism of breast cancer metastasis. Sodium channel 1.5(NaV1.5) and the GTPase Rac1 are factors related to the degree of malignancy of breast tumors. The expression of NaV1.5 and the activation of Rac1 are both involved in EMT. In addition, NaV1.5 can change the plasma membrane potential (Vm) by promoting the inflow of Na+ to depolarize the cell membrane, induce the activation of Rac1 and produce a cascade of reactions that lead to EMT in breast cancer cells; this sequence of events further induces the movement, migration and invasion of tumor cells and affects the prognosis of breast cancer patients. In this paper, the roles of NaV1.5 and Rac1 in EMT-mediated breast cancer progression were reviewed.
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Affiliation(s)
- Zhuocen Zha
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
- Oncology department, Guizhou Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guiyang, Guizhou, 550000, China
| | - Fei Ge
- Department of Breast Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Na Li
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
| | - Shijun Zhang
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
| | - Chenxi Wang
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
| | - Fuhong Gong
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
| | - Jingge Miao
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
| | - Wenlin Chen
- First-Class Discipline Team of Kunming Medical University, Third Department of Breast Surgery, Peking University Cancer Hospital Yunnan, Yunnan Cancer Hospital, The Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China.
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13
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Beevors LI, Sundar S, Foster PA. Steroid metabolism and hormonal dynamics in normal and malignant ovaries. Essays Biochem 2024; 68:491-507. [PMID: 38994724 PMCID: PMC11625866 DOI: 10.1042/ebc20240028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/18/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024]
Abstract
The ovaries are key steroid hormone production sites in post-pubertal females. However, current research on steroidogenic enzymes, endogenous hormone concentrations and their effects on healthy ovarian function and malignant development is limited. Here, we discuss the importance of steroid enzymes in normal and malignant ovaries, alongside hormone concentrations, receptor expression and action. Key enzymes include STS, 3β-HSD2, HSD17B1, ARK1C3, and aromatase, which influence ovarian steroidal action. Both androgen and oestrogen action, via their facilitating enzyme, drives ovarian follicle activation, development and maturation in healthy ovarian tissue. In ovarian cancer, some data suggest STS and oestrogen receptor α may be linked to aggressive forms, while various oestrogen-responsive factors may be involved in ovarian cancer metastasis. In contrast, androgen receptor expression and action vary across ovarian cancer subtypes. For future studies investigating steroidogenesis and steroidal activity in ovarian cancer, it is necessary to differentiate between disease subtypes for a comprehensive understanding.
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Affiliation(s)
- Lucy I Beevors
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, U.K
| | - Sudha Sundar
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, U.K
| | - Paul A Foster
- Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, U.K
- Centre for Diabetes, Endocrinology, and Metabolism, Birmingham Health Partners, Birmingham, U.K
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14
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Jiang RY, Zhu JY, Zhang HP, Yu Y, Dong ZX, Zhou HH, Wang X. STAT3: Key targets of growth-promoting receptor positive breast cancer. Cancer Cell Int 2024; 24:356. [PMID: 39468521 PMCID: PMC11520424 DOI: 10.1186/s12935-024-03541-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/17/2024] [Indexed: 10/30/2024] Open
Abstract
Breast cancer has become the malignant tumor with the first incidence and the second mortality among female cancers. Most female breast cancers belong to luminal-type breast cancer and HER2-positive breast cancer. These breast cancer cells all have different driving genes, which constantly promote the proliferation and metastasis of breast cancer cells. Signal transducer and activator of transcription 3 (STAT3) is an important breast cancer-related gene, which can promote the progress of breast cancer. It has been proved in clinical and basic research that over-expressed and constitutively activated STAT3 is involved in the progress, proliferation, metastasis and chemotherapy resistance of breast cancer. STAT3 is an important key target in luminal-type breast cancer and HER2-positive cancer, which has an important impact on the curative effect of related treatments. In breast cancer, the activation of STAT3 will change the spatial position of STAT3 protein and cause different phenotypic changes of breast cancer cells. In the current basic research and clinical research, small molecule inhibitors activated by targeting STAT3 can effectively treat breast cancer, and enhance the efficacy level of related treatment methods for luminal-type and HER2-positive breast cancers.
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Affiliation(s)
- Rui-Yuan Jiang
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Jia-Yu Zhu
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Huan-Ping Zhang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
- Department of Graduate Student, Wenzhou Medical University, No.270, Xueyuan West Road, Lucheng District, Wenzhou, 325027, Zhejiang, China
| | - Yuan Yu
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China
| | - Zhi-Xin Dong
- Department of Oncology, The First Affiliated Hospital of Guangxi University of Chinese Medicine, No.89-9, Dongge Road, Qingxiu District, Nanning, 530000, Guangxi, China
| | - Huan-Huan Zhou
- The Second School of Clinical Medicine, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China.
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
| | - Xiaojia Wang
- Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
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15
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de Juan A, Tabtim-On D, Coillard A, Becher B, Goudot C, Segura E. The aryl hydrocarbon receptor shapes monocyte transcriptional responses to interleukin-4 by prolonging STAT6 binding to promoters. Sci Signal 2024; 17:eadn6324. [PMID: 39405377 DOI: 10.1126/scisignal.adn6324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 05/25/2024] [Accepted: 09/04/2024] [Indexed: 10/25/2024]
Abstract
Cytokines induce functional and metabolic adaptations in immune cells, typically through transcriptional responses that can be influenced by other extracellular signals and by intracellular factors. The binding of the cytokine interleukin-4 (IL-4) to its receptor induces the phosphorylation and activation of the transcription factor STAT6. The aryl hydrocarbon receptor (AhR), a transcription factor activated by various endogenous and microbe-derived metabolites, modulates the responses of immune cells to danger signals or inflammatory mediators such as cytokines. Here, we investigated cross-talk between the AhR and signaling stimulated by IL-4 in human and mouse monocytes. AhR activation was required for a subset of IL-4-induced transcriptional responses and inhibited the IL-4-induced metabolic switch to fatty acid β-oxidation. The promoters of the genes that were induced by IL-4 in an AhR-dependent manner lacked canonical AhR binding sites, implying a nongenomic mechanism of AhR action. Mechanistically, AhR activation reduced the activity of SHP-1, a phosphatase that targets and inhibits STAT6, and prolonged STAT6 phosphorylation and binding to specific target loci, thus extending the duration of STAT6 activity. Our results identify AhR as a key player in the molecular control of responses to IL-4 in monocytes and suggest a nongenomic mechanism through which AhR ligands may influence the functional responses of cells to IL-4.
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Affiliation(s)
- Alba de Juan
- Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, Paris, France
| | - Darawan Tabtim-On
- Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, Paris, France
| | - Alice Coillard
- Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, Paris, France
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, 8057 Zurich, Switzerland
| | - Christel Goudot
- Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, Paris, France
| | - Elodie Segura
- Institut Curie, PSL Research University, INSERM, U932, 26 rue d'Ulm, Paris, France
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16
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Jefferson W, Wang T, Padilla-Banks E, Williams C. Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression. Nucleic Acids Res 2024; 52:10897-10917. [PMID: 39166489 PMCID: PMC11472041 DOI: 10.1093/nar/gkae714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 06/27/2024] [Accepted: 08/06/2024] [Indexed: 08/23/2024] Open
Abstract
Chromatin changes in response to estrogen and progesterone are well established in cultured cells, but how they control gene expression under physiological conditions is largely unknown. To address this question, we examined in vivo estrous cycle dynamics of mouse uterus hormone receptor occupancy, chromatin accessibility and chromatin structure by combining RNA-seq, ATAC-seq, HiC-seq and ChIP-seq. Two estrous cycle stages were chosen for these analyses, diestrus (highest estrogen) and estrus (highest progesterone). Unexpectedly, rather than alternating with each other, estrogen receptor alpha (ERα) and progesterone receptor (PGR) were co-bound during diestrus and lost during estrus. Motif analysis of open chromatin followed by hypoxia inducible factor 2A (HIF2A) ChIP-seq and conditional uterine deletion of this transcription factor revealed a novel role for HIF2A in regulating diestrus gene expression patterns that were independent of either ERα or PGR binding. Proteins in complex with ERα included PGR and cohesin, only during diestrus. Combined with HiC-seq analyses, we demonstrate that complex chromatin architecture changes including enhancer switching are coordinated with ERα and PGR co-binding during diestrus and non-hormone receptor transcription factors such as HIF2A during estrus to regulate most differential gene expression across the estrous cycle.
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Affiliation(s)
- Wendy N Jefferson
- Reproductive & Developmental Biology Laboratory, Research Triangle Park, NC 27709, USA
| | - Tianyuan Wang
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA
| | | | - Carmen J Williams
- Reproductive & Developmental Biology Laboratory, Research Triangle Park, NC 27709, USA
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17
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Grand RS, Pregnolato M, Baumgartner L, Hoerner L, Burger L, Schübeler D. Genome access is transcription factor-specific and defined by nucleosome position. Mol Cell 2024; 84:3455-3468.e6. [PMID: 39208807 PMCID: PMC11420395 DOI: 10.1016/j.molcel.2024.08.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 06/14/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024]
Abstract
Mammalian gene expression is controlled by transcription factors (TFs) that engage sequence motifs in a chromatinized genome, where nucleosomes can restrict DNA access. Yet, how nucleosomes affect individual TFs remains unclear. Here, we measure the ability of over one hundred TF motifs to recruit TFs in a defined chromosomal locus in mouse embryonic stem cells. This identifies a set sufficient to enable the binding of TFs with diverse tissue specificities, functions, and DNA-binding domains. These chromatin-competent factors are further classified when challenged to engage motifs within a highly phased nucleosome. The pluripotency factors OCT4-SOX2 preferentially engage non-nucleosomal and entry-exit motifs, but not nucleosome-internal sites, a preference that also guides binding genome wide. By contrast, factors such as BANP, REST, or CTCF engage throughout, causing nucleosomal displacement. This supports that TFs vary widely in their sensitivity to nucleosomes and that genome access is TF specific and influenced by nucleosome position in the cell.
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Affiliation(s)
- Ralph Stefan Grand
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; Zentrum für Molekulare Biologie der Universität Heidelberg (ZMBH), DKFZ-ZMBH Alliance, 69120 Heidelberg, Germany
| | - Marco Pregnolato
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4003 Basel, Switzerland
| | - Lisa Baumgartner
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
| | - Leslie Hoerner
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland
| | - Lukas Burger
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; Swiss Institute of Bioinformatics, 4058 Basel, Switzerland
| | - Dirk Schübeler
- Friedrich Miescher Institute for Biomedical Research, 4058 Basel, Switzerland; Faculty of Sciences, University of Basel, 4003 Basel, Switzerland.
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18
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Forbes AN, Xu D, Cohen S, Pancholi P, Khurana E. Discovery of therapeutic targets in cancer using chromatin accessibility and transcriptomic data. Cell Syst 2024; 15:824-837.e6. [PMID: 39236711 PMCID: PMC11415227 DOI: 10.1016/j.cels.2024.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 09/22/2023] [Accepted: 08/08/2024] [Indexed: 09/07/2024]
Abstract
Most cancer types lack targeted therapeutic options, and when first-line targeted therapies are available, treatment resistance is a huge challenge. Recent technological advances enable the use of assay for transposase-accessible chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) on patient tissue in a high-throughput manner. Here, we present a computational approach that leverages these datasets to identify drug targets based on tumor lineage. We constructed gene regulatory networks for 371 patients of 22 cancer types using machine learning approaches trained with three-dimensional genomic data for enhancer-to-promoter contacts. Next, we identified the key transcription factors (TFs) in these networks, which are used to find therapeutic vulnerabilities, by direct targeting of either TFs or the proteins that they interact with. We validated four candidates identified for neuroendocrine, liver, and renal cancers, which have a dismal prognosis with current therapeutic options.
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Affiliation(s)
- Andre Neil Forbes
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Duo Xu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Sandra Cohen
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Priya Pancholi
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA
| | - Ekta Khurana
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065, USA; Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10065, USA.
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19
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Zhang Y, Ding X, Zhang X, Li Y, Xu R, Li HJ, Zuo D, Chen G. Unveiling the contribution of tumor-associated macrophages in driving epithelial-mesenchymal transition: a review of mechanisms and therapeutic Strategies. Front Pharmacol 2024; 15:1404687. [PMID: 39286635 PMCID: PMC11402718 DOI: 10.3389/fphar.2024.1404687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024] Open
Abstract
Tumor-associated macrophages (TAMs), fundamental constituents of the tumor microenvironment (TME), significantly influence cancer development, primarily by promoting epithelial-mesenchymal transition (EMT). EMT endows cancer cells with increased motility, invasiveness, and resistance to therapies, marking a pivotal juncture in cancer progression. The review begins with a detailed exposition on the origins of TAMs and their functional heterogeneity, providing a foundational understanding of TAM characteristics. Next, it delves into the specific molecular mechanisms through which TAMs induce EMT, including cytokines, chemokines and stromal cross-talking. Following this, the review explores TAM-induced EMT features in select cancer types with notable EMT characteristics, highlighting recent insights and the impact of TAMs on cancer progression. Finally, the review concludes with a discussion of potential therapeutic targets and strategies aimed at mitigating TAM infiltration and disrupting the EMT signaling network, thereby underscoring the potential of emerging treatments to combat TAM-mediated EMT in cancer. This comprehensive analysis reaffirms the necessity for continued exploration into TAMs' regulatory roles within cancer biology to refine therapeutic approaches and improve patient outcomes.
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Affiliation(s)
- Yijia Zhang
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Xiaofei Ding
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
| | - Xue Zhang
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Ye Li
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Rui Xu
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Hai-Jun Li
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
| | - Daiying Zuo
- Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
| | - Guang Chen
- Department of Pharmacy, Taizhou Second People's Hospital (Mental Health Center affiliated to Taizhou University School of Medicine), Taizhou University, Taizhou, Zhejiang, China
- Department of Pharmacology, Taizhou University, Taizhou, Zhejiang, China
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20
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Li M, Chen L, Yu F, Mei H, Ma X, Ding K, Yang Y, Rong Z. CTDSPL2 promotes the progression of non-small lung cancer through PI3K/AKT signaling via JAK1. Cell Death Discov 2024; 10:389. [PMID: 39209829 PMCID: PMC11362329 DOI: 10.1038/s41420-024-02162-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024] Open
Abstract
Carboxy-terminal domain small phosphatase like 2 (CTDSPL2), one of the haloacid dehalogenase phosphatases, is associated with several diseases including cancer. However, the role of CTDSPL2 and its regulatory mechanism in lung cancer remain unclear. Here, we aimed to explore the clinical implications, biological functions, and molecular mechanisms of CTDSPL2 in non-small cell lung cancer (NSCLC). CTDSPL2 was identified as a novel target of the tumor suppressor miR-193a-3p. CTDSPL2 expression was significantly elevated in NSCLC tissues. Database analysis showed that CTDSPL2 expression was negatively correlated with patient survival. Depletion of CTDSPL2 inhibited the proliferation, migration, and invasion of NSCLC cells, as well as tumor growth and metastasis in mouse models. Additionally, silencing of CTDSPL2 enhanced CD4+ T cell infiltration into tumors. Moreover, CTDSPL2 interacted with JAK1 and positively regulated JAK1 expression. Subsequent experiments indicated that CTDSPL2 activated the PI3K/AKT signaling pathway through the upregulation of JAK1, thereby promoting the progression of NSCLC. In conclusion, CTDSPL2 may play an oncogenic role in NSCLC progression by activating PI3K/AKT signaling via JAK1. These findings may provide a potential target for the diagnosis and treatment of NSCLC.
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Affiliation(s)
- Muzi Li
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - La Chen
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Fangfang Yu
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Huijuan Mei
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Xingxing Ma
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Keshuo Ding
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
- Department of Pathology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yanan Yang
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
| | - Ziye Rong
- Department of Immunology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
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21
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Li K, Yang B, Du Y, Ding Y, Shen S, Sun Z, Liu Y, Wang Y, Cao S, Ren W, Wang X, Li M, Zhang Y, Wu J, Zheng W, Yan W, Li L. The HOXC10/NOD1/ERK axis drives osteolytic bone metastasis of pan-KRAS-mutant lung cancer. Bone Res 2024; 12:47. [PMID: 39191757 PMCID: PMC11349752 DOI: 10.1038/s41413-024-00350-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 06/09/2024] [Accepted: 07/12/2024] [Indexed: 08/29/2024] Open
Abstract
While KRAS mutation is the leading cause of low survival rates in lung cancer bone metastasis patients, effective treatments are still lacking. Here, we identified homeobox C10 (HOXC10) as a lynchpin in pan-KRAS-mutant lung cancer bone metastasis. Through RNA-seq approach and patient tissue studies, we demonstrated that HOXC10 expression was dramatically increased. Genetic depletion of HOXC10 preferentially impeded cell proliferation and migration in vitro. The bioluminescence imaging and micro-CT results demonstrated that inhibition of HOXC10 significantly reduced bone metastasis of KRAS-mutant lung cancer in vivo. Mechanistically, the transcription factor HOXC10 activated NOD1/ERK signaling pathway to reprogram epithelial-mesenchymal transition (EMT) and bone microenvironment by activating the NOD1 promoter. Strikingly, inhibition of HOXC10 in combination with STAT3 inhibitor was effective against KRAS-mutant lung cancer bone metastasis by triggering ferroptosis. Taken together, these findings reveal that HOXC10 effectively alleviates pan-KRAS-mutant lung cancer with bone metastasis in the NOD1/ERK axis-dependent manner, and support further development of an effective combinatorial strategy for this kind of disease.
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Affiliation(s)
- Kun Li
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
- Health Science Center, East China Normal University, Shanghai, 200241, China
- Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China
| | - Bo Yang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yingying Du
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yi Ding
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Shihui Shen
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
- Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China
| | - Zhengwang Sun
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Yun Liu
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yuhan Wang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Siyuan Cao
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Wenjie Ren
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiangyu Wang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Mengjuan Li
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Yunpeng Zhang
- School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Juan Wu
- Department of Pharmacy The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Wei Zheng
- Orthopaedic Department of Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
- Department of Orthopedics, General Hospital of Western Theater Command, Chengdu, 610000, China.
- College of Medicine, Southwest Jiaotong University, Chengdu, 610031, P. R. China.
| | - Wangjun Yan
- Department of Musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Lei Li
- Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, 401120, China.
- School of Life Sciences, East China Normal University, Shanghai, 200241, China.
- Joint Center for Translational Medicine, Shanghai Fifth People's Hospital, Fudan University and School of Life Science, East China Normal University, Shanghai, 200240, China.
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22
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Xie Y, Xiao D, Li D, Peng M, Peng W, Duan H, Yang X. Combined strategies with PARP inhibitors for the treatment of BRCA wide type cancer. Front Oncol 2024; 14:1441222. [PMID: 39156700 PMCID: PMC11327142 DOI: 10.3389/fonc.2024.1441222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/19/2024] [Indexed: 08/20/2024] Open
Abstract
Genomic instability stands out as a pivotal hallmark of cancer, and PARP inhibitors (PARPi) emerging as a groundbreaking class of targeted therapy drugs meticulously crafted to inhibit the repair of DNA single-strand breaks(SSB) in tumor cells. Currently, PARPi have been approved for the treatment of ovarian cancer, pancreatic cancer, breast cancer, and prostate cancer characterized by homologous recombination(HR) repair deficiencies due to mutations in BRCA1/2 or other DNA repair associated genes and acquiring the designation of breakthrough therapy. Nonetheless, PARPi exhibit limited efficacy in the majority of HR-proficient BRCA1/2 wild-type cancers. At present, the synergistic approach of combining PARPi with agents that induce HR defects, or with chemotherapy and radiotherapy to induce substantial DNA damage, significantly enhances the efficacy of PARPi in BRCA wild-type or HR-proficient patients, supporting extension the use of PARPi in HR proficient patients. Therefore, we have summarized the effects and mechanisms of the combined use of drugs with PARPi, including the combination of PARPi with HR defect-inducing drugs such as ATRi, CHKi, HR indirectly inducing drugs like VEGFRi, CDKi, immune checkpoint inhibitors and drugs instigating DNA damage such as chemotherapy or radiotherapy. In addition, this review discusses several ongoing clinical trials aimed at analyzing the clinical application potential of these combined treatment strategies.
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Affiliation(s)
- Yijun Xie
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Di Xiao
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Duo Li
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Mei Peng
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Wei Peng
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Huaxin Duan
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
| | - Xiaoping Yang
- Department of Oncology, Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Key Laboratory of Protein Chemistry and Developmental Biology of Fish of Ministry of Education, Hunan Normal University, Changsha, Hunan, China
- Department of Pharmacy, Hunan Normal University, Changsha, Hunan, China
- School of Medicine, Hunan Normal University, Changsha, Hunan, China
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23
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Tao W, Xufeng Y, Xianmei C, Mengrou Q, Jieqiong W, Mingqi Q. Exploring the Mechanism of Myrrh in the Treatment of Breast Cancer Based on Network Pharmacology and Cell Experiments. Chem Biol Drug Des 2024; 104:e14604. [PMID: 39147995 DOI: 10.1111/cbdd.14604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 06/23/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
This study aimed to investigate the mechanism of action of myrrh in breast cancer (BC) treatment and identify its effective constituents. Data on the compounds and targets of myrrh were collected from the TCMSP, PubChem, and Swiss Target Prediction databases. BC-related targets were obtained from the Genecard database. A protein-protein interaction (PPI) analysis, gene ontology (GO) enrichment, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted on the intersecting targets of the disease and drug. The key targets of myrrh in BC treatment were identified based on the PPI network. The active constituents of myrrh were determined through reverse-screening using the top 20 KEGG pathways. Macromolecular docking studies, molecular dynamic (MD) simulations, and cell assays were utilized to validate the active constituents and critical targets. Network pharmacology indicated that VEGFA, TP53, ESR1, EGFR, and AKT1 are key targets of myrrh. Pelargonidin chloride, Quercetin, and Naringenin were identified as the active constituents of myrrh. Macromolecular docking showed that Quercetin and Naringenin have strong docking capabilities with ESR1. The results of MD simulation experiments align with those of molecular docking experiments. Cell and western blot assays demonstrated that Quercetin and Naringenin could inhibit MCF-7 cells and significantly reduce the expression of ESR1 protein. The findings reveal the active constituents, key targets, and molecular mechanisms of myrrh in BC treatment, providing scientific evidence that supports the role of myrrh in BC therapy. Furthermore, the results suggest that network pharmacology predictions require experimental validation for reliability.
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Affiliation(s)
- Wu Tao
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of Traditional Chinese Medicine, Research and Innovation Team of Emotional Diseases and Syndrome Research, Shandong University of Traditional Chinese Medicine, Jinan, China
- Emotional Disease Syndrome Innovative Chinese Medicine Research Young Scientific Research and Innovation Team, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu Xufeng
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of Traditional Chinese Medicine, Research and Innovation Team of Emotional Diseases and Syndrome Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Chen Xianmei
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of Traditional Chinese Medicine, Research and Innovation Team of Emotional Diseases and Syndrome Research, Shandong University of Traditional Chinese Medicine, Jinan, China
- Emotional Disease Syndrome Innovative Chinese Medicine Research Young Scientific Research and Innovation Team, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qu Mengrou
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
- College of Traditional Chinese Medicine, Research and Innovation Team of Emotional Diseases and Syndrome Research, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wang Jieqiong
- Emotional Disease Syndrome Innovative Chinese Medicine Research Young Scientific Research and Innovation Team, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Qiao Mingqi
- College of Traditional Chinese Medicine, Research and Innovation Team of Emotional Diseases and Syndrome Research, Shandong University of Traditional Chinese Medicine, Jinan, China
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24
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Du M, Liu Y, Cao J, Li X, Wang N, He Q, Zhang L, Zhao B, Dugarjaviin M. Food from Equids-Commercial Fermented Mare's Milk (Koumiss) Products: Protective Effects against Alcohol Intoxication. Foods 2024; 13:2344. [PMID: 39123538 PMCID: PMC11312395 DOI: 10.3390/foods13152344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/12/2024] Open
Abstract
Fermented mare's milk (koumiss), a traditional Central Asian dairy product derived from fermented mare's milk, is renowned for its unique sour taste and texture. It has long been consumed by nomadic tribes for its nutritional and medicinal benefits. This study aimed to comprehensively analyze the protective effects of koumiss against alcohol-induced harm across behavioral, hematological, gastrointestinal, hepatic, and reproductive dimensions using a mouse model. Optimal intoxicating doses of alcohol and koumiss doses were determined, and their effects were explored through sleep tests and blood indicator measurements. Pretreatment with koumiss delayed inebriation, accelerated sobering, and reduced mortality in mice, mitigating alcohol's impact on blood ethanol levels and various physiological parameters. Histopathological and molecular analyses further confirmed koumiss's protective role against alcohol-induced damage in the liver, stomach, small intestine, and reproductive system. Transcriptomic studies on reproductive damage indicated that koumiss exerts its benefits by influencing mitochondrial and ribosomal functions and also shows promise in mitigating alcohol's effects on the reproductive system. In summary, koumiss emerges as a potential natural agent for protection against alcohol-induced harm, opening avenues for future research in this field.
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Affiliation(s)
- Ming Du
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Yuanyi Liu
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Jialong Cao
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Xinyu Li
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Na Wang
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Qianqian He
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Lei Zhang
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Bilig Zhao
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Manglai Dugarjaviin
- Key Laboratory of Equus Germplasm Innovation, Ministry of Agriculture and Rural Affairs, Hohhot 010018, China; (M.D.); (Y.L.); (J.C.); (X.L.); (N.W.); (Q.H.); (L.Z.); (B.Z.)
- Inner Mongolia Key Laboratory of Equine Science Research and Technology Innovation, Inner Mongolia Agricultural University, Hohhot 010018, China
- Equus Research Center, Inner Mongolia Agricultural University, Hohhot 010018, China
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25
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Xue Y, Chen Y, Sun S, Tong X, Chen Y, Tang S, Wang X, Bi S, Qiu Y, Zhao Q, Qin Z, Xu Q, Ai Y, Chen L, Zhang B, Liu Z, Ji M, Lang M, Chen L, Xu G, Hu L, Ye D, Ji H. TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition. J Exp Med 2024; 221:e20240111. [PMID: 38805014 PMCID: PMC11129275 DOI: 10.1084/jem.20240111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 03/21/2024] [Accepted: 04/05/2024] [Indexed: 05/29/2024] Open
Abstract
Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.
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Affiliation(s)
- Yun Xue
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- University of Chinese Academy of Sciences, Beijing, China
| | - Yuting Chen
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Sijia Sun
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Xinyuan Tong
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yujia Chen
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Shijie Tang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Xue Wang
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Simin Bi
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Yuqin Qiu
- Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
| | - Qiqi Zhao
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
| | - Zhen Qin
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Qin Xu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Yingjie Ai
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Leilei Chen
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Beizhen Zhang
- University of Chinese Academy of Sciences, Beijing, China
| | - Zhijie Liu
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Minbiao Ji
- Department of Physics, State Key Laboratory of Surface Physics, Academy for Engineering and Technology, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Shanghai, China
| | - Meidong Lang
- Key Laboratory of Advanced Polymeric Materials, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, China
- Department of General Surgery and Laboratory of General Surgery, Xinhua Hospital, Affiliated to School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Luonan Chen
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China
| | - Guoliang Xu
- State Key Laboratory of Molecular Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
- Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Chinese Academy of Medical Sciences (RU069), Shanghai, China
| | - Liang Hu
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Dan Ye
- Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism (Ministry of Science and Technology), and Molecular and Cell Biology Laboratory, Institutes of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
| | - Hongbin Ji
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
- Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
- School of Life Science and Technology, Shanghai Tech University, Shanghai, China
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26
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Li Q, Zhou L, Xia D, Wang J. Rheumatoid arthritis reduces the risk of colorectal cancer through immune inflammation mediation. J Cell Mol Med 2024; 28:e18515. [PMID: 38961677 PMCID: PMC11222658 DOI: 10.1111/jcmm.18515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/19/2024] [Accepted: 06/19/2024] [Indexed: 07/05/2024] Open
Abstract
There is a close relationship between immune-mediated inflammation and cancer, and there is still controversy over whether rheumatoid arthritis (RA) increases the risk of malignancy. We first used Mendelian randomization (MR) analysis to explore the potential causal relationship between RA and pan-cancer. And verify the effect of immune-mediated inflammation on cancer through intermediate MR analysis. Then we extracted the standardized incidence rate of malignancy in RA patients relative to the general population through large-scale meta-analysis. Finally, we performed pan-cancer analysis on the RA related genes obtained from MR analysis. And perform immune related analysis on key genes to reveal the association between RA and malignancy. The MR analysis demonstrated a negative correlation between RA and pan-cancer (p = 0.008). Autoimmune traits were the main mediating variable for the causal relationship between RA and pan-cancer. Based on the results of the meta-analysis, we validated that RA reduces the risk of developing colorectal cancer (SIR = 0.69, 95% CI 0.53-0.85). Pan-cancer analysis also showed that high expression of RA related genes was negatively correlated with colon adenocarcinoma. IL6R was the gene with the highest correlation among them, and its correlation with immune cells was higher in colorectal cancer than in other malignancy. Our MR study provides evidence that RA was associated with reduced risk of colorectal cancer. This effect is caused by immune-mediated inflammation, with IL6R being a key regulatory gene.
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Affiliation(s)
- Qifan Li
- Department of OrthopaedicsThe Affiliated Suqian First People's Hospital of Nanjing Medical UniversitySuqianChina
| | - Liang Zhou
- Department of OrthopaedicLianshui county People's HospitalHuai'anChina
| | - Dan Xia
- Department of RespiratoryThe Affiliated Wuxi Fifth Hospital of Jiangnan UniversityWuxiChina
| | - Jiaqian Wang
- Department of OrthopaedicZhongshan Hospital, Fudan UniversityShanghaiChina
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Pu W, Ma C, Wang B, Zhu W, Chen H. The "Heater" of "Cold" Tumors-Blocking IL-6. Adv Biol (Weinh) 2024; 8:e2300587. [PMID: 38773937 DOI: 10.1002/adbi.202300587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 03/13/2024] [Indexed: 05/24/2024]
Abstract
The resolution of inflammation is not simply the end of the inflammatory response but rather a complex process that involves various cells, inflammatory factors, and specialized proresolving mediators following the occurrence of inflammation. Once inflammation cannot be cleared by the body, malignant tumors may be induced. Among them, IL-6, as an immunosuppressive factor, activates a variety of signal transduction pathways and induces tumorigenesis. Monitoring IL-6 can be used for the diagnosis, efficacy evaluation and prognosis of tumor patients. In terms of treatment, improving the efficacy of targeted and immunotherapy remains a major challenge. Blocking IL-6 and its mediated signaling pathways can regulate the tumor immune microenvironment and enhance immunotherapy responses by activating immune cells. Even transform "cold" tumors that are difficult to respond to immunotherapy into immunogenic "hot" tumors, acting as a "heater" for "cold" tumors, restarting the tumor immune cycle, and reducing immunotherapy-related toxic reactions and drug resistance. In clinical practice, the combined application of IL-6 inhibition with targeted therapy and immunotherapy may produce synergistic results. Nevertheless, additional clinical trials are imperative to further validate the safety and efficacy of this therapeutic approach.
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Affiliation(s)
- Weigao Pu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Chenhui Ma
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Bofang Wang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Weidong Zhu
- General Surgery Department of Lintao County People's Hospital in Gansu Province, Lanzhou, Gansu, 730030, China
| | - Hao Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, 730030, China
- Department of Tumour Surgery, Lanzhou University Second Hospital, Lanzhou, 730030, China
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, Gansu, 730030, China
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Li Z, Zhao H, Hu H, Shang H, Ren Y, Qiu W, Su H, Lyu H, Chen X. Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer. Chin J Cancer Res 2024; 36:306-321. [PMID: 38988489 PMCID: PMC11230884 DOI: 10.21147/j.issn.1000-9604.2024.03.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/30/2024] [Indexed: 07/12/2024] Open
Abstract
Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.
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Affiliation(s)
- Zhifei Li
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Huan Zhao
- Henan University of Traditional Chinese Medicine, Zhengzhou 450046, China
| | - Huihui Hu
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Haili Shang
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Yongjing Ren
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Wenhui Qiu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Hao Su
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, China
| | - Huifang Lyu
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Xiaobing Chen
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
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Razavipour SF, Yoon H, Jang K, Kim M, Nawara HM, Bagheri A, Huang WC, Shin M, Zhao D, Zhou Z, Van Boven D, Briegel K, Morey L, Ince TA, Johnson M, Slingerland JM. C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer. Nat Commun 2024; 15:5152. [PMID: 38886396 PMCID: PMC11183067 DOI: 10.1038/s41467-024-48742-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Accepted: 05/14/2024] [Indexed: 06/20/2024] Open
Abstract
In many cancers, a stem-like cell subpopulation mediates tumor initiation, dissemination and drug resistance. Here, we report that cancer stem cell (CSC) abundance is transcriptionally regulated by C-terminally phosphorylated p27 (p27pT157pT198). Mechanistically, this arises through p27 co-recruitment with STAT3/CBP to gene regulators of CSC self-renewal including MYC, the Notch ligand JAG1, and ANGPTL4. p27pTpT/STAT3 also recruits a SIN3A/HDAC1 complex to co-repress the Pyk2 inhibitor, PTPN12. Pyk2, in turn, activates STAT3, creating a feed-forward loop increasing stem-like properties in vitro and tumor-initiating stem cells in vivo. The p27-activated gene profile is over-represented in STAT3 activated human breast cancers. Furthermore, mammary transgenic expression of phosphomimetic, cyclin-CDK-binding defective p27 (p27CK-DD) increases mammary duct branching morphogenesis, yielding hyperplasia and microinvasive cancers that can metastasize to liver, further supporting a role for p27pTpT in CSC expansion. Thus, p27pTpT interacts with STAT3, driving transcriptional programs governing stem cell expansion or maintenance in normal and cancer tissues.
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Affiliation(s)
- Seyedeh Fatemeh Razavipour
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Hyunho Yoon
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
- Department of Medical and Biological Sciences, The Catholic University of Korea, Bucheon-si, South Korea
| | - Kibeom Jang
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Minsoon Kim
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Hend M Nawara
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA
| | - Amir Bagheri
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA
| | - Wei-Chi Huang
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA
| | - Miyoung Shin
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Dekuang Zhao
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Zhiqun Zhou
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Derek Van Boven
- John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Karoline Briegel
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
- Department of Surgery, University of Miami, Miller School of Medicine, Miami, Fl, USA
| | - Lluis Morey
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA
- John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Tan A Ince
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Michael Johnson
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA
| | - Joyce M Slingerland
- Cancer Host Interactions Program, Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, Washington DC, USA.
- Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Fl, USA.
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Chiang YC, Selvam P, Liu YX, Shih PC, Chen NF, Kuo HM, Lin HYH, Wen ZH, Chen WF. STAT3 phosphorylation inhibitor Bt354 exhibits anti-neoplastic activity in glioblastoma multiforme cells. ENVIRONMENTAL TOXICOLOGY 2024; 39:3292-3303. [PMID: 38415901 DOI: 10.1002/tox.24178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Revised: 11/28/2023] [Accepted: 01/18/2024] [Indexed: 02/29/2024]
Abstract
The high mortality rate of glioblastoma multiforme (GBM), a lethal primary brain tumor, is attributable to postsurgical recurrence. STAT3, an oncogenic protein, is a signal transducer and transcription activator encourages cancer cell migration and proliferation, which results in resistance to therapy. STAT3 inhibition reduces cancer metastasis and improves patient prognosis. Bt354, a small molecule STAT inhibitor, exhibits significant cytotoxic and anti-proliferative activities against certain cancer types. Here, we demonstrated that exposure of GBM cells (U87 MG) to Bt354 had a significant, concentration-dependent growth suppression. Bt354 also induced apoptosis and downregulated the expression of the epithelial-mesenchymal transition genes. Therefore, this study suggests the potential of Bt354 for treating GBM owing to its ability to induce cytotoxicity.
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Affiliation(s)
- Yi-Chun Chiang
- Department of Surgery, Division of Neurosurgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
| | - Padhmavathi Selvam
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - You-Xuan Liu
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Po-Chang Shih
- Institute of BioPharmaceutical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Nan-Fu Chen
- Department of Surgery, Division of Neurosurgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Hsiao-Mei Kuo
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
| | - Hugo You-Hsien Lin
- Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan
- Division of Nephrology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Zhi-Hong Wen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Wu-Fu Chen
- Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung, Taiwan
- Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung, Taiwan
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31
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Thakur C, Qiu Y, Pawar A, Chen F. Epigenetic regulation of breast cancer metastasis. Cancer Metastasis Rev 2024; 43:597-619. [PMID: 37857941 DOI: 10.1007/s10555-023-10146-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Breast cancer is the most frequently diagnosed malignancy and the second leading cause of cancer-related mortality among women worldwide. Recurrent metastasis is associated with poor patient outcomes and poses a significant challenge in breast cancer therapies. Cancer cells adapting to a new tissue microenvironment is the key event in distant metastasis development, where the disseminating tumor cells are likely to acquire genetic and epigenetic alterations during the process of metastatic colonization. Despite several decades of research in this field, the exact mechanisms governing metastasis are not fully understood. However, emerging body of evidence indicates that in addition to genetic changes, epigenetic reprogramming of cancer cells and the metastatic niche are paramount toward successful metastasis. Here, we review and discuss the latest knowledge about the salient attributes of metastasis and epigenetic regulation in breast cancer and crucial research domains that need further investigation.
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Affiliation(s)
- Chitra Thakur
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
| | - Yiran Qiu
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Aashna Pawar
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA
| | - Fei Chen
- Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY, 11794, USA.
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32
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He W, Loganathan N, Tran A, Belsham DD. Npy transcription is regulated by noncanonical STAT3 signaling in hypothalamic neurons: Implication with lipotoxicity and obesity. Mol Cell Endocrinol 2024; 586:112179. [PMID: 38387703 DOI: 10.1016/j.mce.2024.112179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 01/27/2024] [Accepted: 02/05/2024] [Indexed: 02/24/2024]
Abstract
Neuropeptide Y (Npy) is an abundant neuropeptide expressed in the central and peripheral nervous systems. NPY-secreting neurons in the hypothalamic arcuate nucleus regulate energy homeostasis, and Npy mRNA expression is regulated by peripheral nutrient and hormonal signals like leptin, interleukin-6 (IL-6), and fatty acids. This study demonstrates that IL-6, which phosphorylates tyrosine 705 (Y705) of STAT3, decreased Npy mRNA in arcuate immortalized hypothalamic neurons. In parallel, inhibitors of STAT3-Y705 phosphorylation, stattic and cucurbitacin I, robustly upregulated Npy mRNA. Chromatin-immunoprecipitation showed high baseline total STAT3 binding to multiple regulatory regions of the Npy gene, which are decreased by IL-6 exposure. The STAT3-Npy interaction was further examined in obesity-related pathologies. Notably, in four different hypothalamic neuronal models where palmitate potently stimulated Npy mRNA, Socs3, a specific STAT3 activity marker, was downregulated and was negatively correlated with Npy mRNA levels (R2 = 0.40, p < 0.001), suggesting that disrupted STAT3 signaling is involved in lipotoxicity-mediated dysregulation of Npy. Finally, human NPY SNPs that map to human obesity or body mass index were investigated for potential STAT3 binding sites. Although none of the SNPs were linked to direct STAT3 binding, analysis show that rs17149106 (-602 G > T) is located on an upstream enhancer element of NPY, where the variant is predicted to disrupt validated binding of KLF4, a known inhibitory cofactor of STAT3 and downstream effector of leptin signaling. Collectively, this study demonstrates that STAT3 signaling negatively regulates Npy transcription, and that disruption of this interaction may contribute to metabolic disorders.
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Affiliation(s)
- Wenyuan He
- Departments of Physiology, University of Toronto, Ontario, Canada
| | | | - Andy Tran
- Departments of Physiology, University of Toronto, Ontario, Canada
| | - Denise D Belsham
- Departments of Physiology, University of Toronto, Ontario, Canada; Departments of Medicine, University of Toronto, Ontario, Canada.
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Hou M, Li H, He T, Hui S, Dai W, Hou X, Zhao J, Zhao J, Wen J, Kan W, Xiao X, Zhan X, Bai Z. Icariside I reduces breast cancer proliferation, apoptosis, invasion, and metastasis probably through inhibiting IL-6/STAT3 signaling pathway. J Pharm Pharmacol 2024; 76:499-513. [PMID: 37971302 DOI: 10.1093/jpp/rgad103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 10/23/2023] [Indexed: 11/19/2023]
Abstract
OBJECTIVES Breast cancer is a common malignancy in women. More than 90% of breast cancer deaths are caused by metastasis. Epimedii Folium (EF) is a commonly used herb with anti-tumor benefits, but its underlying mechanisms and active components for breast cancer prevention are little understood. This study assessed the therapeutic role of Icariside I (ICS I) in Epimedium flavonoids (EF) on lung metastasis of breast cancer, including the underlying mechanism. METHODS Western blot, RT-qPCR, wound healing assay, colony formation assay, and flow cytometry were used to investigate the inhibition of breast cancer cells growth and migration by EF and ICS I through disrupting the IL-6/STAT3 pathway. Combined with 4T1 breast cancer model in mice, Western blot, RT-qPCR, Hematoxylin and Eosin staining, immunohistochemistry were used to evaluate the therapeutic role of ICS I in proliferation, apoptosis, invasion, and metastasis of breast cancer. KEY FINDINGS EF can inhibit STAT3 phosphorylation and reduce the colony formation and migration of breast cancer cells. Detecting the active ingredients in EF, we found ICS I can reduce the activation of STAT3 in 4T1 breast cancer cells, impair colony formation and migration. Moreover, ICS I induced cells G1 phase arrest and modulated Cyclin D1, CDK4, bcl-2, and bax to inhibit proliferation and survival of breast cancer cells. Similarly, the in vivo studies demonstrated that ICS I significantly suppressed tumor development and lung metastasis in the 4T1 mouse model. Tumor cells in vehicle group were arranged in a spoke-like pattern with obvious heterogeneity, and multinucleated tumor giant cells were seen. But, the tumor cells in the ICS I group were disorganized and necrotic lysis was seen in some areas. In ICS I-treated group, tumors' STAT3 phosphorylation level, IL-6, Cyclin D1, CDK4, bcl-2, and vimentin expression were downregulated, bax and cleaved caspase 3 expression were upregulated. In the lung tissue, we could find less metastasis of breast cancer cells and less lung injury in the ICS I group. Besides, the expression of metastasis-related genes MMP9 and vimentin was decreased in the lung tissue of ICS I group. CONCLUSIONS These findings suggest that ICS I can inhibit breast cancer proliferation, apoptosis, invasion and metastasis probably via targeting IL-6/STAT3 pathway. Therefore, ICS I has the potential to become an innovative therapeutic candidate to breast cancer prevention and treatment.
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Affiliation(s)
- Manting Hou
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Hui Li
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
| | - Tingting He
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- Department of Integrated Chinese and Western Medicine, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Siwen Hui
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Wenzhang Dai
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xiaorong Hou
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jing Zhao
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jia Zhao
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Jincai Wen
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Wen Kan
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Xiaohe Xiao
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
| | - Xiaoyan Zhan
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
| | - Zhaofang Bai
- Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
- China Military Institute of Chinese Materia, The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China
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Priscilla L, Yoo C, Jang S, Park S, Lim G, Kim T, Lee DY. Immunotherapy targeting the obese white adipose tissue microenvironment: Focus on non-communicable diseases. Bioact Mater 2024; 35:461-476. [PMID: 38404641 PMCID: PMC10884763 DOI: 10.1016/j.bioactmat.2024.01.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/14/2024] [Accepted: 01/30/2024] [Indexed: 02/27/2024] Open
Abstract
Obesity triggers inflammatory responses in the microenvironment of white adipose tissue, resulting in chronic systemic inflammation and the subsequent development of non-communicable diseases, including type 2 diabetes, coronary heart disease, and breast cancer. Current therapy approaches for obesity-induced non-communicable diseases persist in prioritizing symptom remission while frequently overlooking the criticality of targeting and alleviating inflammation at its source. Accordingly, this review highlights the importance of the microenvironment of obese white adipose tissue and the promising potential of employing immunotherapy to target it as an effective therapeutic approach for non-communicable diseases induced by obesity. Additionally, this review discusses the challenges and offers perspective about the immunotherapy targeting the microenvironment of obese white adipose tissue.
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Affiliation(s)
- Lia Priscilla
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Chaerim Yoo
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Seonmi Jang
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Sewon Park
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Gayoung Lim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Taekyun Kim
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
| | - Dong Yun Lee
- Department of Bioengineering, College of Engineering, and BK FOUR Biopharmaceutical Innovation Leader for Education and Research Group, Hanyang University, Seoul, 04763, Republic of Korea
- Institute of Nano Science and Technology (INST) & Institute for Bioengineering and Biopharmaceutical Research (IBBR), Hanyang University, Seoul, 04763, Republic of Korea
- Elixir Pharmatech Inc., Seoul, 07463, Republic of Korea
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35
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Ai L, Yi N, Qiu C, Huang W, Zhang K, Hou Q, Jia L, Li H, Liu L. Revolutionizing breast cancer treatment: Harnessing the related mechanisms and drugs for regulated cell death (Review). Int J Oncol 2024; 64:46. [PMID: 38456493 PMCID: PMC11000534 DOI: 10.3892/ijo.2024.5634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2023] [Accepted: 02/22/2024] [Indexed: 03/09/2024] Open
Abstract
Breast cancer arises from the malignant transformation of mammary epithelial cells under the influence of various carcinogenic factors, leading to a gradual increase in its prevalence. This disease has become the leading cause of mortality among female malignancies, posing a significant threat to the health of women. The timely identification of breast cancer remains challenging, often resulting in diagnosis at the advanced stages of the disease. Conventional therapeutic approaches, such as surgical excision, chemotherapy and radiotherapy, exhibit limited efficacy in controlling the progression and metastasis of the disease. Regulated cell death (RCD), a process essential for physiological tissue cell renewal, occurs within the body independently of external influences. In the context of cancer, research on RCD primarily focuses on cuproptosis, ferroptosis and pyroptosis. Mounting evidence suggests a marked association between these specific forms of RCD, and the onset and progression of breast cancer. For example, a cuproptosis vector can effectively bind copper ions to induce cuproptosis in breast cancer cells, thereby hindering their proliferation. Additionally, the expression of ferroptosis‑related genes can enhance the sensitivity of breast cancer cells to chemotherapy. Likewise, pyroptosis‑related proteins not only participate in pyroptosis, but also regulate the tumor microenvironment, ultimately leading to the death of breast cancer cells. The present review discusses the unique regulatory mechanisms of cuproptosis, ferroptosis and pyroptosis in breast cancer, and the mechanisms through which they are affected by conventional cancer drugs. Furthermore, it provides a comprehensive overview of the significance of these forms of RCD in modulating the efficacy of chemotherapy and highlights their shared characteristics. This knowledge may provide novel avenues for both clinical interventions and fundamental research in the context of breast cancer.
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Affiliation(s)
- Leyu Ai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Department of Clinical Medicine, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Na Yi
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Chunhan Qiu
- Department of Clinical Medicine, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Wanyi Huang
- Medical College, Yan'an University, Yan'an, Shaanxi 716000, P.R. China
| | - Keke Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Qiulian Hou
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Long Jia
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Hui Li
- Central Laboratory of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
| | - Ling Liu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
- Xinjiang Key Laboratory of Molecular Biology for Endemic Diseases, Urumqi, Xinjiang Uygur Autonomous Region 830017, P.R. China
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Wu M, Huang X, Wu B, Zhu M, Zhu Y, Yu L, Lan T, Liu J. The endonuclease FEN1 mediates activation of STAT3 and facilitates proliferation and metastasis in breast cancer. Mol Biol Rep 2024; 51:553. [PMID: 38642158 DOI: 10.1007/s11033-024-09524-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 04/04/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND The metastasis accounts for most deaths from breast cancer (BRCA). Understanding the molecular mechanisms of BRCA metastasis is urgently demanded. Flap Endonuclease 1 (FEN1), a pivotal factor in DNA metabolic pathways, contributes to tumor growth and drug resistance, however, little is known about the role of FEN1 in BRCA metastasis. METHODS AND RESULTS In this study, FEN1 expression and its clinical correlation in BRCA were investigated using bioinformatics, showing being upregulated in BRCA samples and significant relationships with tumor stage, node metastasis, and prognosis. Immunohistochemistry (IHC) staining of local BRCA cohort indicated that the ratio of high FEN1 expression in metastatic BRCA tissues rose over that in non-metastatic tissues. The assays of loss-of-function and gain-of-function showed that FEN1 enhanced BRCA cell proliferation, migration, invasion, xenograft growth as well as lung metastasis. It was further found that FEN1 promoted the aggressive behaviors of BRCA cells via Signal Transducer and Activator of Transcription 3 (STAT3) activation. Specifically, the STAT3 inhibitor Stattic thwarted the FEN1-induced enhancement of migration and invasion, while the activator IL-6 rescued the decreased migration and invasion caused by FEN1 knockdown. Additionally, overexpression of FEN1 rescued the inhibitory effect of nuclear factor-κB (NF-κB) inhibitor BAY117082 on phosphorylated STAT3. Simultaneously, the knockdown of FEN1 attenuated the phosphorylation of STAT3 promoted by the NF-κB activator tumor necrosis factor α (TNF-α). CONCLUSIONS These results indicate a novel mechanism that NF-κB-driven FEN1 contributes to promoting BRCA growth and metastasis by STAT3 activation.
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Affiliation(s)
- Min Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China.
| | - Xiaoshan Huang
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China
| | - Benmeng Wu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China
| | - Miaolin Zhu
- Department of Pathology, Jiangsu Cancer Hospital, Nanjing, China
| | - Yaqin Zhu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China
| | - Lin Yu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China
| | - Ting Lan
- School of Medical Technology, Xuzhou Medical University, Xuzhou, 221004, China.
| | - Jingjing Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225009, China.
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, China.
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Kang F, Chen Z, Liao C, Wu Y, Li G, Xie C, Lin H, Huang L, Tian Y, Wang Z, Chen S. Escherichia coli-Induced cGLIS3-Mediated Stress Granules Activate the NF-κB Pathway to Promote Intrahepatic Cholangiocarcinoma Progression. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306174. [PMID: 38368261 PMCID: PMC11040339 DOI: 10.1002/advs.202306174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 02/01/2024] [Indexed: 02/19/2024]
Abstract
Patients with concurrent intrahepatic cholangiocarcinoma (ICC) and hepatolithiasis generally have poor prognoses. Hepatolithiasis is once considered the primary cause of ICC, although recent insights indicate that bacteria in the occurrence of hepatolithiasis can promote the progression of ICC. By constructing in vitro and in vivo ICC models and patient-derived organoids (PDOs), it is shown that Escherichia coli induces the production of a novel RNA, circGLIS3 (cGLIS3), which promotes tumor growth. cGLIS3 binds to hnRNPA1 and G3BP1, resulting in the assembly of stress granules (SGs) and suppression of hnRNPA1 and G3BP1 ubiquitination. Consequently, the IKKα mRNA is blocked in SGs, decreasing the production of IKKα and activating the NF-κB pathway, which finally results in chemoresistance and produces metastatic phenotypes of ICC. This study shows that a combination of Icaritin (ICA) and gemcitabine plus cisplatin (GP) chemotherapy can be a promising treatment strategy for ICC.
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Affiliation(s)
- Feng‐Ping Kang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Zhi‐Wen Chen
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Cheng‐Yu Liao
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatobiliary Pancreatic SurgeryFujian Provincial HospitalFuzhou350001China
| | - Yong‐Ding Wu
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Ge Li
- Department of Hepatobiliary Surgery and Fujian Institute of Hepatobiliary SurgeryFujian Medical University Union HospitalFuzhou350001China
| | - Cheng‐Ke Xie
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Hong‐Yi Lin
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
| | - Long Huang
- Department of Hepatobiliary Pancreatic SurgeryFujian Provincial HospitalFuzhou350001China
| | - Yi‐Feng Tian
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatobiliary Pancreatic SurgeryFujian Provincial HospitalFuzhou350001China
| | - Zu‐Wei Wang
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatobiliary Pancreatic SurgeryFujian Provincial HospitalFuzhou350001China
| | - Shi Chen
- Shengli Clinical Medical College of Fujian Medical UniversityFuzhou350001China
- Department of Hepatobiliary Pancreatic SurgeryFujian Provincial HospitalFuzhou350001China
- Fujian Key Laboratory of GeriatricsFujian Provincial HospitalFuzhou350001China
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Yang J, Li N, Zhao X, Guo W, Wu Y, Nie C, Yuan Z. WP1066, a small molecule inhibitor of STAT3, chemosensitizes paclitaxel-resistant ovarian cancer cells to paclitaxel by simultaneously inhibiting the activity of STAT3 and the interaction of STAT3 with Stathmin. Biochem Pharmacol 2024; 221:116040. [PMID: 38311257 DOI: 10.1016/j.bcp.2024.116040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/29/2023] [Accepted: 01/30/2024] [Indexed: 02/10/2024]
Abstract
Paclitaxel is widely used to treat cancer, however, drug resistance limits its clinical utility. STAT3 is constitutively activated in some cancers, and contributes to chemotherapy resistance. Currently, several STAT3 inhibitors including WP1066 are used in cancer clinical trials. However, whether WP1066 reverses paclitaxel resistance and the mechanismremains unknown. Here, we report that in contrast to paclitaxel-sensitive parental cells, the expressions of several pro-survival BCL2 family members such as BCL-2, BCL-XL and MCL-1 are higher in paclitaxel-resistant ovarian cancer cells. Meanwhile, STAT3 is constitutively activated while stathmin loses its activity in paclitaxel-resistant cells. Importantly, WP1066 amplifies the inhibition of cell proliferation, colony-forming ability and apoptosis of ovarian cancer cells induced by paclitaxel. Mechanistically, WP1066, on the one hand, interferes the STAT3/Stathmin interaction, causing unleash of STAT3/Stathmin from microtubule, thus destroying microtubule stability. This process results in reduction of Ac-α-tubulin, further causing MCL-1 reduction. On the other hand, WP1066 inhibits phosphorylation of STAT3 by JAK2, and blocks its nuclear translocation, therefore repressing the transcription of pro-survival targets such as BCL-2, BCL-XL and MCL-1. Finally, the two pathways jointly promote cell death. Our findings reveal a new mechanism wherein WP1066 reverses paclitaxel-resistance of ovarian cancer cells by dually inhibiting STAT3 activity and STAT3/Stathmin interaction, which may layfoundation for WP1066 combined with paclitaxel in treating paclitaxel-resistant ovarian cancer.
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Affiliation(s)
- Jun Yang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Nanjing Li
- Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinyu Zhao
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenhao Guo
- Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yang Wu
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chunlai Nie
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhu Yuan
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Baumgartner F, Bamopoulos SA, Faletti L, Hsiao HJ, Holz M, Gonzalez-Menendez I, Solé-Boldo L, Horne A, Gosavi S, Özerdem C, Singh N, Liebig S, Ramamoorthy S, Lehmann M, Demel U, Kühl AA, Wartewig T, Ruland J, Wunderlich FT, Schick M, Walther W, Rose-John S, Haas S, Quintanilla-Martinez L, Feske S, Ehl S, Glauben R, Keller U. Activation of gp130 signaling in T cells drives T H17-mediated multi-organ autoimmunity. Sci Signal 2024; 17:eadc9662. [PMID: 38377177 DOI: 10.1126/scisignal.adc9662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 01/31/2024] [Indexed: 02/22/2024]
Abstract
The IL-6-gp130-STAT3 signaling axis is a major regulator of inflammation. Activating mutations in the gene encoding gp130 and germline gain-of-function mutations in STAT3 (STAT3GOF) are associated with multi-organ autoimmunity, severe morbidity, and adverse prognosis. To dissect crucial cellular subsets and disease biology involved in activated gp130 signaling, the gp130-JAK-STAT3 axis was constitutively activated using a transgene, L-gp130, specifically targeted to T cells. Activating gp130 signaling in T cells in vivo resulted in fatal, early onset, multi-organ autoimmunity in mice that resembled human STAT3GOF disease. Female mice had more rapid disease progression than male mice. On a cellular level, gp130 signaling induced the activation and effector cell differentiation of T cells, promoted the expansion of T helper type 17 (TH17) cells, and impaired the activity of regulatory T cells. Transcriptomic profiling of CD4+ and CD8+ T cells from these mice revealed commonly dysregulated genes and a gene signature that, when applied to human transcriptomic data, improved the segregation of patients with transcriptionally diverse STAT3GOF mutations from healthy controls. The findings demonstrate that increased gp130-STAT3 signaling leads to TH17-driven autoimmunity that phenotypically resembles human STAT3GOF disease.
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Affiliation(s)
- Francis Baumgartner
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité (Junior) (Digital) Clinician Scientist Program, 10178 Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Stefanos A Bamopoulos
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité (Junior) (Digital) Clinician Scientist Program, 10178 Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Laura Faletti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Hsiang-Jung Hsiao
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Maximilian Holz
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Irene Gonzalez-Menendez
- Institute of Pathology and Neuropathology, Comprehensive Cancer Center, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," Eberhard Karls University, 72076 Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
| | - Llorenç Solé-Boldo
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany
| | - Arik Horne
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany
- Department of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Sanket Gosavi
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Ceren Özerdem
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany
| | - Nikita Singh
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Sven Liebig
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Senthilkumar Ramamoorthy
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, 79110 Freiburg, Germany
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Malte Lehmann
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- iPATH.Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Uta Demel
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité (Junior) (Digital) Clinician Scientist Program, 10178 Berlin, Germany
| | - Anja A Kühl
- iPATH.Berlin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Campus Benjamin Franklin, 12203 Berlin, Germany
| | - Tim Wartewig
- Institute for Clinical Chemistry and Pathobiochemistry, Technische Universität München, 81675 Munich, Germany
- Center of Molecular and Cellular Oncology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Jürgen Ruland
- Institute for Clinical Chemistry and Pathobiochemistry, Technische Universität München, 81675 Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich, a partnership between DKFZ and Technische Universität München, 81675 Munich, Germany
| | - Frank T Wunderlich
- Obesity and Cancer, Max Planck Institute for Metabolism Research, 50931 Cologne, Germany
| | - Markus Schick
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
| | - Wolfgang Walther
- Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine, Robert-Rössle Str. 10, 13125 Berlin, Germany
- EPO GmbH Berlin-Buch, Robert-Rössle-Str. 10, 13125 Berlin, Germany
| | - Stefan Rose-John
- Institute of Biochemistry, Christian-Albrechts-Universität zu Kiel, 24118 Kiel, Germany
| | - Simon Haas
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Berlin Institute of Health (BIH) at Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
- Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 10115 Berlin, Germany
- Division of Stem Cells and Cancer, Deutsches Krebsforschungszentrum (DKFZ) and DKFZ - ZMBH Alliance, 69120 Heidelberg, Germany
- Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), 69120 Heidelberg, Germany
| | - Leticia Quintanilla-Martinez
- Institute of Pathology and Neuropathology, Comprehensive Cancer Center, Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
- Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies," Eberhard Karls University, 72076 Tübingen, Germany
- German Cancer Consortium (DKTK), partner site Tübingen, a partnership between DKFZ and Eberhard Karls University of Tübingen, 72076 Tübingen, Germany
| | - Stefan Feske
- Department of Pathology, New York University School of Medicine, New York, NY 10016, USA
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Rainer Glauben
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
- Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany
- German Cancer Consortium (DKTK), partner site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, 10117 Berlin, Germany
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He B, Guo W, Shi R, Hoffman RD, Luo Q, Hu YJ, Gao J. Ruyong formula improves thymus function of CUMS-stimulated breast cancer mice. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117164. [PMID: 37717843 DOI: 10.1016/j.jep.2023.117164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 08/20/2023] [Accepted: 09/08/2023] [Indexed: 09/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ruyong Formula (RYF) is a famous Chinese herbal formula composed of 10 traditional Chinese herbs. It has been used as a therapeutic agent for breast cancer patients with depressive symptoms in China. However, its underlying pharmacological mechanism remains unclear. AIM OF THE STUDY This study aimed to explore the mechanism of RYF on the changes of thymus immune function in breast cancer body under mood disorders such as depression/anxiety. MATERIALS AND METHODS The chronic unpredictable mild stress (CUMS) was used to stimulate 4T1 breast cancer mice. The behavioral changes, 5-hydroxytryptamine (5-HT) level in brain, cytokeratin 5 (CK5) and 8 (CK8) expression in thymus, the proportion of T cell subsets, the thymic output, phenotypic changes of thymus epithelial cells (TECs), the expression levels of immune-related factors and downstream proteins of TSLP were analyzed after RYF treatment. RESULTS In CUMS stimulated group, the level of 5-HT in brain was significantly increased after RYF treatment. The output function of the thymus was improved, and the number of TECs in the medulla (CK5+), the proportion of CD3+CD4-CD8- (Double negative) and CD3+CD4+CD8+ (Double positive) T cells were all increased. The mRNA level of TSLP in mouse thymus was significantly decreased, but increased for IL-7. The protein levels of TSLP and Vimentin were decreased, but increased for p-STAT3, p-JAK2, E-cadherin, and p-PI3K p55 in vivo. In vitro study was showed the levels of Snail 1, Zeb 1 and Smad increased significantly in TGF-β1 group, and RYF could reverse their expression. CONCLUSIONS RYF could restore the structure and function of the thymus in depressed breast cancer mice by reversing the phenotypic changes of TECs and activating the JAK2/STAT3/PI3K pathway.
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Affiliation(s)
- Bingqian He
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Wenqin Guo
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China; School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Rongzhen Shi
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China; Tangqi Branch of Traditional Chinese Medicine Hospital of Linping District, Hangzhou, Zhejiang, 311106, China.
| | - Robert D Hoffman
- Yo San University of Traditional Chinese Medicine, Los Angeles, CA, 90066, USA.
| | - Qihan Luo
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Yuan-Jia Hu
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, 999078, China.
| | - Jianli Gao
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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41
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Meng Y, Zhou D, Luo Y, Chen J, Li H. An estrogen-regulated long non-coding RNA NCALD promotes luminal breast cancer proliferation by activating GRHL2. Cancer Cell Int 2024; 24:49. [PMID: 38291441 PMCID: PMC10829383 DOI: 10.1186/s12935-024-03245-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 01/25/2024] [Indexed: 02/01/2024] Open
Abstract
PURPOSE Luminal breast cancer (BC) is a prevalent subtype associated with an increased risk of late disease recurrence and mortality. Long noncoding RNAs (lncRNAs) likely play significant roles in regulating tissue-specific gene expression during tumorigenesis. However, the biological function and underlying mechanisms of specific dysregulated lncRNAs in luminal BC remain largely unknown, which has drawn our attention. METHODS The expression pattern of lncRNA NCALD in luminal BC was predicted and validated in collected tissue samples. Following cell transfection with knockdown of lncRNA NCALD and ESR1 and overexpression of GRHL2 and ESR1, we investigated the interactions among lncRNA NCALD, ESR1, and GRHL2. Additionally, their regulatory functions in luminal BC cell biological processes were studied. Subsequently, a xenograft tumor model was prepared for validation. RESULTS Our study identified a specific overexpression of the lncRNA NCALD in luminal BC, which correlated with an unfavorable prognosis. Suppression of lncRNA NCALD or ESR1 led to inhibition of GRHL2 expression, while concurrent overexpression of ESR1 and lncRNA NCALD potentially elevated GRHL2 expression. Mechanistically, ERα may drive the expression of lncRNA NCALD. Furthermore, the 1-151 nt fragment of lncRNA NCALD was found to recruit ERα and interact with its oest-Recep domain located in the promoter region of GRHL2, ultimately inducing GRHL2 transcription. CONCLUSIONS These findings reveal the involvement of lncRNA NCALD and its specific expression pattern in luminal BC. Targeting lncRNA NCALD could be a potential therapeutic strategy for delaying the progression of BC.
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Affiliation(s)
- Yue Meng
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 ZhongShan Road, Guangzhou, 51000, Guangdong, China.
| | - Dianrong Zhou
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 ZhongShan Road, Guangzhou, 51000, Guangdong, China
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 51000, Guangdong, China
| | - Ying Luo
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 ZhongShan Road, Guangzhou, 51000, Guangdong, China
| | - Jierong Chen
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 ZhongShan Road, Guangzhou, 51000, Guangdong, China
| | - Hui Li
- Department of Clinical Laboratory, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 ZhongShan Road, Guangzhou, 51000, Guangdong, China
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Peyvandi S, Bulliard M, Yilmaz A, Kauzlaric A, Marcone R, Haerri L, Coquoz O, Huang YT, Duffey N, Gafner L, Lorusso G, Fournier N, Lan Q, Rüegg C. Tumor-educated Gr1+CD11b+ cells drive breast cancer metastasis via OSM/IL-6/JAK-induced cancer cell plasticity. J Clin Invest 2024; 134:e166847. [PMID: 38236642 PMCID: PMC10940099 DOI: 10.1172/jci166847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 01/17/2024] [Indexed: 03/16/2024] Open
Abstract
Cancer cell plasticity contributes to therapy resistance and metastasis, which represent the main causes of cancer-related death, including in breast cancer. The tumor microenvironment drives cancer cell plasticity and metastasis, and unraveling the underlying cues may provide novel strategies for managing metastatic disease. Using breast cancer experimental models and transcriptomic analyses, we show that stem cell antigen-1 positive (SCA1+) murine breast cancer cells enriched during tumor progression and metastasis had higher in vitro cancer stem cell-like properties, enhanced in vivo metastatic ability, and generated tumors rich in Gr1hiLy6G+CD11b+ cells. In turn, tumor-educated Gr1+CD11b+ (Tu-Gr1+CD11b+) cells rapidly and transiently converted low metastatic SCA1- cells into highly metastatic SCA1+ cells via secreted oncostatin M (OSM) and IL-6. JAK inhibition prevented OSM/IL-6-induced SCA1+ population enrichment, while OSM/IL-6 depletion suppressed Tu-Gr1+CD11b+-induced SCA1+ population enrichment in vitro and metastasis in vivo. Moreover, chemotherapy-selected highly metastatic 4T1 cells maintained high SCA1+ positivity through autocrine IL-6 production, and in vitro JAK inhibition blunted SCA1 positivity and metastatic capacity. Importantly, Tu-Gr1+CD11b+ cells invoked a gene signature in tumor cells predicting shorter overall survival (OS), relapse-free survival (RFS), and lung metastasis in breast cancer patients. Collectively, our data identified OSM/IL-6/JAK as a clinically relevant paracrine/autocrine axis instigating breast cancer cell plasticity and triggering metastasis.
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Affiliation(s)
- Sanam Peyvandi
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Manon Bulliard
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Alev Yilmaz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Annamaria Kauzlaric
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Rachel Marcone
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Lisa Haerri
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Oriana Coquoz
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yu-Ting Huang
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nathalie Duffey
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Laetitia Gafner
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Girieca Lorusso
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Nadine Fournier
- Translational Data Science Group, Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Qiang Lan
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Cell and Tissue Dynamics Research Program, Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
| | - Curzio Rüegg
- Pathology Unit, Department of Oncology, Microbiology and Immunology (OMI), Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
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Lin X, Chi W, Geng X, Jiang Q, Ma B, Dai B, Sui Y, Jiang J. Evaluation of the Mechanism of Yishan Formula in Treating Breast Cancer Based on Network Pharmacology and Experimental Verification. Comb Chem High Throughput Screen 2024; 27:2583-2597. [PMID: 38178684 DOI: 10.2174/0113862073266004231105164321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 08/07/2023] [Accepted: 08/31/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Yishan formula (YSF) has a significant effect on the treatment of breast cancer, which can improve the quality of life and prolong the survival of patients with breast cancer; however, its mechanism of action is unknown. OBJECTIVE In this study, network pharmacology and molecular docking methods have been used to explore the potential pharmacological effects of the YSF, and the predicted targets have been validated by in vitro experiments. METHODS Active components and targets of the YSF were obtained from the TCMSP and Swiss target prediction website. Four databases, namely GeneCards, OMIM, TTD, and DisGeNET, were used to search for disease targets. The Cytoscape v3.9.0 software was utilized to draw the network of drug-component-target and selected core targets. DAVID database was used to analyze the biological functions and pathways of key targets. Finally, molecular docking and in vitro experiments have been used to verify the hub genes. RESULTS Through data collection from the database, 157 active components and 618 genes implicated in breast cancer were obtained and treated using the YSF. After screening, the main active components (kaempferol, quercetin, isorhamnetin, dinatin, luteolin, and tamarixetin) and key genes (AKT1, TP53, TNF, IL6, EGFR, SRC, VEGFA, STAT3, MAPK3, and JUN) were obtained. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the YSF could affect the progression of breast cancer by regulating biological processes, such as signal transduction, cell proliferation and apoptosis, protein phosphorylation, as well as PI3K-Akt, Rap1, MAPK, FOXO, HIF-1, and other related signaling pathways. Molecular docking suggested that IL6 with isorhamnetin, MAPK3 with kaempferol, and EGFR with luteolin have strong binding energy. The experiment further verified that YSF can control the development of breast cancer by inhibiting the expression of the hub genes. CONCLUSION This study showed that resistance to breast cancer may be achieved by the synergy of multiple active components, target genes, and signal pathways, which can provide new avenues for breast cancer-targeted therapy.
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Affiliation(s)
- Xiaoyue Lin
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Wencheng Chi
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150000, China
| | - Xue Geng
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Qinghui Jiang
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Baozhu Ma
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Bowen Dai
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
| | - Yutong Sui
- Shenzhen Hospital of Southern Medical University, Shenzhen, 518110, China
| | - Jiakang Jiang
- Heilongjiang University of Chinese Medicine, Harbin, 150000, China
- The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, 150000, China
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Pascual G, Majem B, Benitah SA. Targeting lipid metabolism in cancer metastasis. Biochim Biophys Acta Rev Cancer 2024; 1879:189051. [PMID: 38101461 DOI: 10.1016/j.bbcan.2023.189051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 11/29/2023] [Accepted: 12/04/2023] [Indexed: 12/17/2023]
Abstract
This review delves into the most recent research on the metabolic adaptability of cancer cells and examines how their metabolic functions can impact their progression into metastatic forms. We emphasize the growing significance of lipid metabolism and dietary lipids within the tumor microenvironment, underscoring their influence on tumor progression. Additionally, we present an outline of the interplay between metabolic processes and the epigenome of cancer cells, underscoring the importance regarding the metastatic process. Lastly, we examine the potential of targeting metabolism as a therapeutic approach in combating cancer progression, shedding light on innovative drugs/targets currently undergoing preclinical evaluation.
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Affiliation(s)
- Gloria Pascual
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
| | - Blanca Majem
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
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Huang S, Wang Y, Zhu Q, Guo H, Hong Z, Zhong S. Network Pharmacology and Intestinal Microbiota Analysis Revealing the Mechanism of Punicalagin Improving Bacterial Enteritis. Curr Comput Aided Drug Des 2024; 20:104-120. [PMID: 37246319 PMCID: PMC10641859 DOI: 10.2174/1573409919666230526165501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 03/07/2023] [Accepted: 04/12/2023] [Indexed: 05/30/2023]
Abstract
BACKGROUND The Chinese medicine punicalagin (Pun), the most important active ingredient in pomegranate peel, has significant bacteriostatic and anti-inflammatory properties. The potential mechanisms of Pun for bacterial enteritis, however, are unknown. OBJECTIVE The goal of our research is to investigate the mechanism of Pun in the treatment of bacterial enteritis using computer-aided drug technology, as well as to investigate the intervention effect of Pun on mice with bacterial enteritis using intestinal flora sequencing. METHODS The targets of Pun and Bacterial enteritis were obtained by using the specific database, and cross-targets were screened among these targets, followed by PPI and enrichment analysis of the targets. Furthermore, the degree of binding between Pun and key targets was predicted through molecular docking. After successfully establishing the bacterial enteritis model in vivo, mice were randomly assigned to groups. They were treated for 7 days, the symptoms were observed daily, and the daily DAI and body weight change rate were calculated. Following administration, the intestinal tissue was removed, and the contents were separated. The tight junction protein expression was detected in the small intestine by the immunohistochemical method; ELISA and Western Blot (WB) were performed to detect the expressions of tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) in the serum and intestinal wall of mice. The 16S rRNA sequence was used to determine the composition and diversity of the intestinal flora of mice. RESULTS In total, 130 intersection targets of Pun and disease were screened by network pharmacology. The enrichment analysis showed cross genes were closely related and enriched in the cancer regulation and the TNF signal pathway. The active components of Pun could specifically bind to the core targets TNF, IL-6, etc., determined from molecular docking results. In vivo experiment results showed that the symptoms in the PUN group mice were alleviated, and the expression levels of TNF-α and IL-6 were significantly reduced. A Pun can cause substantial changes in the intestinal flora of mice in terms of structure and function. CONCLUSION Pun plays a multi-target role in alleviating bacterial enteritis by regulating intestinal flora.
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Affiliation(s)
- Shuyun Huang
- Tissue and Embryo Department, Wannan Medical College, Wuhu, 241002, China
| | - Ying Wang
- Tissue and Embryo Department, Wannan Medical College, Wuhu, 241002, China
| | - Qingsong Zhu
- Computer and Information Department, Hohai University, Nanjing, 210024, China
| | - Hongmin Guo
- Tissue and Embryo Department, Wannan Medical College, Wuhu, 241002, China
| | - Zongyuan Hong
- Tissue and Embryo Department, Wannan Medical College, Wuhu, 241002, China
| | - Shuzhi Zhong
- Tissue and Embryo Department, Wannan Medical College, Wuhu, 241002, China
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Sitte Z, Miranda Buzetta AA, Jones SJ, Lin ZW, Whitman NA, Lockett MR. Paper-Based Coculture Platform to Evaluate the Effects of Fibroblasts on Estrogen Signaling in ER+ Breast Cancers. ACS MEASUREMENT SCIENCE AU 2023; 3:479-487. [PMID: 38145029 PMCID: PMC10740124 DOI: 10.1021/acsmeasuresciau.3c00032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 12/26/2023]
Abstract
Cell-based assays enable molecular-level studies of cellular responses to drug candidates or potential toxins. Transactivation assays quantify the activation or inhibition of nuclear receptors, key transcriptional regulators of gene targets in mamalian cells. One such assay couples the expression of luciferase to the transcriptional activity of estrogen receptor-alpha (ERα). While this assay is regularly used to screen for agonists and antagonists of the estrogen signaling pathway, the setup relies on monolayer cultures in which cells are plated directly onto the surface of cell-compatible plasticware. The tumor microenvironment is more than a collection of cancerous cells and is profoundly influenced by tissue architecture, the presence of extracellular matrices, and intercellular signaling molecules produced by non-cancerous neighboring cells (e.g., fibroblasts). There exists a need for three-dimensional culture platforms that can be rapidly prototyped to assess new configurations and readily produced in the large numbers needed for translational studies and screening applications. Here, we demonstrate the utility of the paper-based culture platform to probe the effects of intercellular signaling between two cell types. We used paper scaffolds to generate tumor-like environments, forming a defined volume of breast cancer cells suspended in collagen. By placing the paper scaffolds in commercial 96-well plates, we compared monocultures of only breast cancer cells with coculture configurations containing fibroblasts in different locations that mimicked the stages of breast cancer progression. We show that ERα transactivation in the T47D-KBluc cell line is affected by the presence, number, and proximity of fibroblasts, and is a consequence of intercellular signaling molecules. After screening a small library of fibroblast-secreted signaling molecules, we showed that interleukin-6 (IL-6) was the primary driver of reduced estradiol sensitivity. These effects were mitigated in the coculture configurations by the addition of an IL-6 neutralizing antibody. We also assessed estrogen receptor expression and transcriptional regulation, further demonstrating the utility of the paper-based platform for detailed mechanistic studies.
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Affiliation(s)
- Zachary
R. Sitte
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
| | - Abel Andre Miranda Buzetta
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
| | - Sarina J. Jones
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
| | - Zhi-Wei Lin
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
| | - Nathan Ashbrook Whitman
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
| | - Matthew R. Lockett
- Department
of Chemistry, University of North Carolina
at Chapel Hill, Kenan and Caudill Laboratories, 125 South Road, Chapel Hill, North Carolina 27599-3290, United States
- Lineberger
Comprehensive Cancer Center, University
of North Carolina at Chapel Hill, 450 West Drive, Chapel Hill, North Carolina 27599-7295, United States
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Ramesh V, Gollavilli PN, Pinna L, Siddiqui MA, Turtos AM, Napoli F, Antonelli Y, Leal‐Egaña A, Havelund JF, Jakobsen ST, Boiteux EL, Volante M, Færgeman NJ, Jensen ON, Siersbæk R, Somyajit K, Ceppi P. Propionate reinforces epithelial identity and reduces aggressiveness of lung carcinoma. EMBO Mol Med 2023; 15:e17836. [PMID: 37766669 PMCID: PMC10701619 DOI: 10.15252/emmm.202317836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 09/05/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
The epithelial-to-mesenchymal transition (EMT) plays a central role in the development of cancer metastasis and resistance to chemotherapy. However, its pharmacological treatment remains challenging. Here, we used an EMT-focused integrative functional genomic approach and identified an inverse association between short-chain fatty acids (propionate and butanoate) and EMT in non-small cell lung cancer (NSCLC) patients. Remarkably, treatment with propionate in vitro reinforced the epithelial transcriptional program promoting cell-to-cell contact and cell adhesion, while reducing the aggressive and chemo-resistant EMT phenotype in lung cancer cell lines. Propionate treatment also decreased the metastatic potential and limited lymph node spread in both nude mice and a genetic NSCLC mouse model. Further analysis revealed that chromatin remodeling through H3K27 acetylation (mediated by p300) is the mechanism underlying the shift toward an epithelial state upon propionate treatment. The results suggest that propionate administration has therapeutic potential in reducing NSCLC aggressiveness and warrants further clinical testing.
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Affiliation(s)
- Vignesh Ramesh
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
- Interdisciplinary Centre for Clinical ResearchUniversity Hospital Erlangen, FAU‐Erlangen‐NurembergErlangenGermany
| | - Paradesi Naidu Gollavilli
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
- Interdisciplinary Centre for Clinical ResearchUniversity Hospital Erlangen, FAU‐Erlangen‐NurembergErlangenGermany
| | - Luisa Pinna
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | | | | | - Francesca Napoli
- Department of Oncology at San Luigi HospitalUniversity of TurinTurinItaly
| | - Yasmin Antonelli
- Institute for Molecular Systems Engineering and Advanced MaterialsHeidelberg UniversityHeidelbergGermany
| | - Aldo Leal‐Egaña
- Institute for Molecular Systems Engineering and Advanced MaterialsHeidelberg UniversityHeidelbergGermany
| | - Jesper Foged Havelund
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | | | - Elisa Le Boiteux
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | - Marco Volante
- Department of Oncology at San Luigi HospitalUniversity of TurinTurinItaly
| | - Nils Joakim Færgeman
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | - Ole N Jensen
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | - Rasmus Siersbæk
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | - Kumar Somyajit
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
| | - Paolo Ceppi
- Department of Biochemistry and Molecular BiologyUniversity of Southern DenmarkOdenseDenmark
- Interdisciplinary Centre for Clinical ResearchUniversity Hospital Erlangen, FAU‐Erlangen‐NurembergErlangenGermany
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Liu Y, John P, Nishitani K, Cui J, Nishimura CD, Christin JR, Couturier N, Ren X, Wei Y, Pulanco MC, Galbo PM, Zhang X, Fu W, Cui W, Bartholdy BA, Zheng D, Lauvau G, Fineberg SA, Oktay MH, Zang X, Guo W. A SOX9-B7x axis safeguards dedifferentiated tumor cells from immune surveillance to drive breast cancer progression. Dev Cell 2023; 58:2700-2717.e12. [PMID: 37963469 PMCID: PMC10842074 DOI: 10.1016/j.devcel.2023.10.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 09/15/2023] [Accepted: 10/20/2023] [Indexed: 11/16/2023]
Abstract
How dedifferentiated stem-like tumor cells evade immunosurveillance remains poorly understood. We show that the lineage-plasticity regulator SOX9, which is upregulated in dedifferentiated tumor cells, limits the number of infiltrating T lymphocytes in premalignant lesions of mouse basal-like breast cancer. SOX9-mediated immunosuppression is required for the progression of in situ tumors to invasive carcinoma. SOX9 induces the expression of immune checkpoint B7x/B7-H4 through STAT3 activation and direct transcriptional regulation. B7x is upregulated in dedifferentiated tumor cells and protects them from immunosurveillance. B7x also protects mammary gland regeneration in immunocompetent mice. In advanced tumors, B7x targeting inhibits tumor growth and overcomes resistance to anti-PD-L1 immunotherapy. In human breast cancer, SOX9 and B7x expression are correlated and associated with reduced CD8+ T cell infiltration. This study, using mouse models, cell lines, and patient samples, identifies a dedifferentiation-associated immunosuppression mechanism and demonstrates the therapeutic potential of targeting the SOX9-B7x pathway in basal-like breast cancer.
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Affiliation(s)
- Yu Liu
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Peter John
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Kenta Nishitani
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Jihong Cui
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Christopher D Nishimura
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - John R Christin
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Nicole Couturier
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Xiaoxin Ren
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Yao Wei
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Marc C Pulanco
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Phillip M Galbo
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Xusheng Zhang
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Wenyan Fu
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Wei Cui
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Boris A Bartholdy
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Departments of Neurology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Gregoire Lauvau
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Susan A Fineberg
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA
| | - Maja H Oktay
- Department of Pathology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY 10467, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Gruss-Lipper Biophotonic Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Xingxing Zang
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Urology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | - Wenjun Guo
- Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Montefiore Einstein Comprehensive Cancer Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
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Xiang X, Kuang W, Yu C, Li Y, Su Q, Tian Y, Li J. Tex10 interacts with STAT3 to regulate hepatocellular carcinoma growth and metastasis. Mol Carcinog 2023; 62:1974-1989. [PMID: 37792308 DOI: 10.1002/mc.23629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 07/07/2023] [Accepted: 08/18/2023] [Indexed: 10/05/2023]
Abstract
Testis expression 10 (Tex10) is reported to be associated with tumorigenesis in several types of cancer types, but its role in hepatocellular carcinoma (HCC) metastasis has not been investigated. In this study, the expression of Tex10 in the HCC cell line and tissue microarray was determined by Western blot and immunohistochemistry (IHC), respectively. RNA sequencing-based transcriptome analysis was performed to identify the Tex10-mediated biological process. Cell Counting Kit-8, colony formation, transwell assays, xenograft tumor growth, and lung metastasis experiments in nude mice were applied to assess the effects of Tex10 on cell proliferation, migration, invasion, and metastasis. The underlying mechanisms were further investigated using dual-luciferase reporter, co-immunoprecipitation, immunofluorescence, and chromatin immunoprecipitation assays. We found that Tex10 was upregulated in HCC tumor tissues compared to adjacent normal tissues, with its expression correlated with a poor prognosis. Gene ontology function enrichment analysis revealed alterations in several biological processes in response to Tex10 knockdown, especially cell motility and cell migration. Functional studies demonstrated that Tex10 promotes HCC cell proliferation, migration, invasion, and metastasis in vitro and in vivo. Moreover, Tex10 was shown to regulate invasion and epithelial-mesenchymal transition via signal transducer and activator of transcription 3 (STAT3) signaling. Mechanistically, Tex10 was found to interact with STAT3 and promote its transcriptional activity. In addition, we found that Tex10 promotes p300-mediated STAT3 acetylation, while p300 silencing abolishes Tex10-enhanced STAT3 transcriptional activity. Together, these findings indicate that Tex10 functions as an oncogene by upregulating STAT3 activity, thus suggesting that Tex10 may serve as a prognostic biomarker and/or therapeutic target for HCC patients.
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Affiliation(s)
- Xiaocong Xiang
- Institute of Hepato-Biliary-Pancreatic-Intestinal Disease, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
- Institute of Tissue Engineering and Stem Cells, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Wei Kuang
- Institute of Materia Medica, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Chunlei Yu
- Institute of Materia Medica, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Yuqi Li
- Institute of Materia Medica, School of Pharmacy, North Sichuan Medical College, Nanchong, China
| | - Qiang Su
- Department of Pharmacy, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Yunhong Tian
- Department of General Surgery, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Jingdong Li
- Department of Hepatobiliary Surgery, Academician (Expert) Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong, China
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50
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Llorente A, Blasco MT, Espuny I, Guiu M, Ballaré C, Blanco E, Caballé A, Bellmunt A, Salvador F, Morales A, Nuñez M, Loren G, Imbastari F, Fidalgo M, Figueras-Puig C, Gibler P, Graupera M, Monteiro F, Riera A, Holen I, Avgustinova A, Di Croce L, Gomis RR. MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis. Nat Cell Biol 2023; 25:1833-1847. [PMID: 37945904 PMCID: PMC10709142 DOI: 10.1038/s41556-023-01281-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 10/09/2023] [Indexed: 11/12/2023]
Abstract
MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.
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Affiliation(s)
- Alicia Llorente
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
| | - María Teresa Blasco
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
| | - Irene Espuny
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marc Guiu
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Cecilia Ballaré
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Enrique Blanco
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
| | - Adrià Caballé
- Biostatistics and Bioinformatics Unit, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Anna Bellmunt
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Fernando Salvador
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Andrea Morales
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marc Nuñez
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Guillem Loren
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Francesca Imbastari
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Marta Fidalgo
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
| | - Cristina Figueras-Puig
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Patrizia Gibler
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Mariona Graupera
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
- Endothelial Pathobiology and Microenvironment Group, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
| | - Freddy Monteiro
- Functional Genomics Core Facility, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
| | - Antoni Riera
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain
- Universitat de Barcelona, Barcelona, Spain
| | - Ingunn Holen
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | | | - Luciano Di Croce
- Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
- Universitat Pompeu Fabra (UPF), Barcelona, Spain
| | - Roger R Gomis
- Cancer Science Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
- Universitat de Barcelona, Barcelona, Spain.
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