|
1
|
Wang H, Zhang W, Sun Y, Xu X, Chen X, Zhao K, Yang Z, Liu H. Nanotherapeutic strategies exploiting biological traits of cancer stem cells. Bioact Mater 2025; 50:61-94. [PMID: 40242505 PMCID: PMC12002948 DOI: 10.1016/j.bioactmat.2025.03.016] [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: 11/30/2024] [Revised: 03/08/2025] [Accepted: 03/20/2025] [Indexed: 04/18/2025] Open
Abstract
Cancer stem cells (CSCs) represent a distinct subpopulation of cancer cells that orchestrate cancer initiation, progression, metastasis, and therapeutic resistance. Despite advances in conventional therapies, the persistence of CSCs remains a major obstacle to achieving cancer eradication. Nanomedicine-based approaches have emerged for precise CSC targeting and elimination, offering unique advantages in overcoming the limitations of traditional treatments. This review systematically analyzes recent developments in nanomedicine for CSC-targeted therapy, emphasizing innovative nanomaterial designs addressing CSC-specific challenges. We first provide a detailed examination of CSC biology, focusing on their surface markers, signaling networks, microenvironmental interactions, and metabolic signatures. On this basis, we critically evaluate cutting-edge nanomaterial engineering designed to exploit these CSC traits, including stimuli-responsive nanodrugs, nanocarriers for drug delivery, and multifunctional nanoplatforms capable of generating localized hyperthermia or reactive oxygen species. These sophisticated nanotherapeutic approaches enhance selectivity and efficacy in CSC elimination, potentially circumventing drug resistance and cancer recurrence. Finally, we present an in-depth analysis of current challenges in translating nanomedicine-based CSC-targeted therapies from bench to bedside, offering critical insights into future research directions and clinical implementation. This review aims to provide a comprehensive framework for understanding the intersection of nanomedicine and CSC biology, contributing to more effective cancer treatment modalities.
Collapse
Affiliation(s)
- Hongyu Wang
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Wenjing Zhang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Yun Sun
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xican Xu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Xiaoyang Chen
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Kexu Zhao
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Zhao Yang
- State Key Laboratory of Green Biomanufacturing, Innovation Center of Molecular Diagnostics, College of Life Science and Technology, Beijing University of Chemical Technology, 100029, Beijing, China
| | - Huiyu Liu
- State Key Laboratory of Organic-Inorganic Composites, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, Beijing Key Laboratory of Bioprocess, Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, 100029, Beijing, China
| |
Collapse
|
|
2
|
Yang Y, Gao J, Shi H, Sihto H, Kilpinen S, Vilcot F, Janská L, Jeschonneck J, Cvetanovic T, Höög A, Siarov J, Paoli J, Juhlin CC, Villabona L, Larsson C, Lui WO. IGF2BP3 As a Prognostic Biomarker and Regulator of Metastasis in Merkel Cell Carcinoma. JID INNOVATIONS 2025; 5:100355. [PMID: 40162116 PMCID: PMC11951866 DOI: 10.1016/j.xjidi.2025.100355] [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] [Revised: 02/02/2025] [Accepted: 02/03/2025] [Indexed: 04/02/2025] Open
Abstract
Merkel cell carcinoma (MCC) is an aggressive skin cancer with frequent metastasis; however, effective treatment options for advanced disease are often lacking. In this study, we investigated the clinical significance and functional impact of IGF2 mRNA-binding protein 3 (IGF2BP3) in MCC. Our results revealed elevated IGF2BP3 expression in metastases compared to that in primary tumors. High IGF2BP3 levels in primary MCCs were associated with shorter disease-specific survival rates. In an MCC xenograft model, the lung metastases exhibited increased IGF2BP3 expression. Functional studies showed that IGF2BP3 primarily regulates MCC cell migration and invasion. We identified 281 direct RNA targets of IGF2BP3 with enriched functions linked to metastasis-related processes, and several targets overlapped with genes differentially expressed between MCC primary tumors and metastases, implying that IGF2BP3 and its targets contribute to tumor progression. Inhibition or silencing of bromodomain-containing protein 4 reduced IGF2BP3 expression, suggesting that bromodomain-containing protein 4 is a potential regulator of IGF2BP3. Our study underscores the role of IGF2BP3 in MCC metastasis and its potential as a prognostic biomarker.
Collapse
Affiliation(s)
- Yajie Yang
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Jiwei Gao
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Hao Shi
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Harri Sihto
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Sami Kilpinen
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - François Vilcot
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Libuse Janská
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Jakob Jeschonneck
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Todor Cvetanovic
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Anders Höög
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Jan Siarov
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - John Paoli
- Department of Dermatology and Venereology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - C. Christofer Juhlin
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Lisa Villabona
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| | - Catharina Larsson
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
- Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Weng-Onn Lui
- Department of Oncology-Pathology, Karolinska Institutet and BioClinicum, Karolinska University Hospital, Solna, Sweden
| |
Collapse
|
|
3
|
Fu Y, Maccioni L, Wang XW, Greten TF, Gao B. Alcohol-associated liver cancer. Hepatology 2024; 80:1462-1479. [PMID: 38607725 DOI: 10.1097/hep.0000000000000890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024]
Abstract
Heavy alcohol intake induces a wide spectrum of liver diseases ranging from steatosis, steatohepatitis, cirrhosis, and HCC. Although alcohol consumption is a well-known risk factor for the development, morbidity, and mortality of HCC globally, alcohol-associated hepatocellular carcinoma (A-HCC) is poorly characterized compared to viral hepatitis-associated HCC. Most A-HCCs develop after alcohol-associated cirrhosis (AC), but the direct carcinogenesis from ethanol and its metabolites to A-HCC remains obscure. The differences between A-HCC and HCCs caused by other etiologies have not been well investigated in terms of clinical prognosis, genetic or epigenetic landscape, molecular mechanisms, and heterogeneity. Moreover, there is a huge gap between basic research and clinical practice due to the lack of preclinical models of A-HCC. In the current review, we discuss the pathogenesis, heterogeneity, preclinical approaches, epigenetic, and genetic profiles of A-HCC, and discuss the current insights into and the prospects for future research on A-HCC. The potential effect of alcohol on cholangiocarcinoma and liver metastasis is also discussed.
Collapse
Affiliation(s)
- Yaojie Fu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Luca Maccioni
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Xin Wei Wang
- Liver Carcinogenesis Section, Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Tim F Greten
- Liver Cancer Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland, USA
- Gastrointestinal Malignancies Section, Thoracic and Gastrointestinal Malignancies Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| |
Collapse
|
|
4
|
Zhou H, Tan L, Zhang B, Kwong DLW, Wong CN, Zhang Y, Ru B, Lyu Y, Siu KTH, Luo J, Yang Y, Liu Q, Chen Y, Zhang W, He C, Jiang P, Qin Y, Liu B, Guan XY. GPRC5A promotes lung colonization of esophageal squamous cell carcinoma. Nat Commun 2024; 15:9950. [PMID: 39550386 PMCID: PMC11569164 DOI: 10.1038/s41467-024-54251-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 11/04/2024] [Indexed: 11/18/2024] Open
Abstract
Emerging evidence suggests that cancer cells may disseminate early, prior to the formation of traditional macro-metastases. However, the mechanisms underlying the seeding and transition of early disseminated cancer cells (DCCs) into metastatic tumors remain poorly understood. Through single-cell RNA sequencing, we show that early lung DCCs from esophageal squamous cell carcinoma (ESCC) exhibit a trophoblast-like 'tumor implantation' phenotype, which enhances their dissemination and supports metastatic growth. Notably, ESCC cells overexpressing GPRC5A demonstrate improved implantation and persistence, resulting in macro-metastases in the lungs. Clinically, elevated GPRC5A level is associated with poorer outcomes in a cohort of 148 ESCC patients. Mechanistically, GPRC5A is found to potentially interact with WWP1, facilitating the polyubiquitination and degradation of LATS1, thereby activating YAP1 signaling pathways essential for metastasis. Importantly, targeting YAP1 axis with CA3 or TED-347 significantly diminishes early implantation and macro-metastases. Thus, the GPRC5A/WWP1/LATS1/YAP1 pathway represents a crucial target for therapeutic intervention in ESCC lung metastases.
Collapse
Grants
- Hong Kong Research Grant Council (RGC) grants including Collaborative Research Funds (C7065-18GF, C7026-18GF and C4039-19GF), Research Impact Fund (R4017-18, R1020-18F and R7022-20), General Research Fund (17119322), Theme-based Research Scheme Fund (T12-703/22-R), the National Natural Science Foundation of China (82072738, 82273483), Shenzhen Key Laboratory for cancer metastasis and personalized therapy (ZDSYS20210623091811035), Shenzhen Science and Technology Program (JCYJ20220818103014030, KQTD20180411185028798, JCYJ20220818103012025), Sanming Project of Medicine in Shenzhen (SZSM202211017), Guangdong Science and Technology Department (2020B1212030004), the Program for Guangdong Introducing Innovative and Entrepreneurial Team (2019BT02Y198)
- National Natural Science Foundation of China (82303160), GuangdongBasic and Applied Basic Research Foundation (2023A1515010109)
Collapse
Affiliation(s)
- Hongyu Zhou
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Licheng Tan
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Baifeng Zhang
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Dora Lai Wan Kwong
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Ching Ngar Wong
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yu Zhang
- Department of Pediatric Oncology, Sun Yat-Sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Beibei Ru
- Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yingchen Lyu
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kin To Hugo Siu
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jie Luo
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yuma Yang
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Qin Liu
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Yixin Chen
- Department of Liver Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Weiguang Zhang
- Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Chaohui He
- Department of Cardiovascular Surgery, Songshan Lake Central Hospital of Dongguan City, Dongguan, China
| | - Peng Jiang
- Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yanru Qin
- Department of Clinical Oncology, the First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Beilei Liu
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
| | - Xin-Yuan Guan
- Department of Clinical Oncology, Centre for Cancer Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- Shenzhen Key Laboratory for cancer metastasis and personalized therapy, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
- Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China.
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, China.
| |
Collapse
|
|
5
|
Zhang W, Liu H, Ren C, Zhang K, Zhang S, Shi S, Li Z, Li J. Deciphering the IGF2BP3-mediated control of ferroptosis: mechanistic insights and therapeutic prospects. Discov Oncol 2024; 15:547. [PMID: 39392532 PMCID: PMC11469981 DOI: 10.1007/s12672-024-01432-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/07/2024] [Indexed: 10/12/2024] Open
Abstract
The rapid expansion of the oncology field has revealed new insights into cell death processes, with a particular emphasis on the role of ferroptosis. Characterized by iron dependency and the accumulation of lipid peroxides and iron within cells, ferroptosis stands out as a unique form of programmed cell demise. This in-depth analysis delves into the pivotal role of IGF2BP3, an RNA-binding protein, in the complex regulatory network of ferroptosis in cancerous cells. By exerting post-transcriptional control over genes associated with iron equilibrium, IGF2BP3 is demonstrated to manage cellular iron concentrations and reactive oxygen species (ROS) equilibrium, thus affecting the destiny of the cell. The correlation between aberrant IGF2BP3 expression and increased aggressiveness, metastatic capacity, and poor prognosis in various cancers is further clarified. The potential of IGF2BP3 as a biomarker for prognosis and a therapeutic agent to enhance cancer cells' vulnerability to ferroptosis is also examined, heralding new strategies in cancer treatment.
Collapse
Affiliation(s)
- Wenjuan Zhang
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Hui Liu
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Changrong Ren
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Kaiqian Zhang
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Shuhan Zhang
- Department of Hepatobiliary Surgery, Air Force Medical Center, PLA, Air Force Medical University, Beijing, China
| | - Shifan Shi
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Zhiyan Li
- Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China
| | - Jian Li
- Department of Hepatobiliary Surgery, Hebei Key Laboratory of Panvascular Diseases, Affiliated Hospital of Chengde Medical University, NO.36 NanYingZi Road, Chengde, 067000, HeBei, China.
| |
Collapse
|
|
6
|
Madaan V, Kollara A, Spaner D, Brown TJ. ISGylation enhances dsRNA-induced interferon response and NFκB signaling in fallopian tube epithelial cells. J Biol Chem 2024; 300:107686. [PMID: 39159817 PMCID: PMC11418117 DOI: 10.1016/j.jbc.2024.107686] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 07/23/2024] [Accepted: 08/07/2024] [Indexed: 08/21/2024] Open
Abstract
Heritable mutations in BRCA1 associate with increased risk of high-grade serous tubo-ovarian cancer. Nongenetic risk factors associated with this cancer, which arises from fallopian tube epithelial (FTE) cells, suggests a role for repetitive ovulation wherein FTE cells are exposed to inflammatory signaling molecules within follicular fluid. We previously reported increased NFκB and EGFR signaling in BRCA1-deficient primary FTE cells, with follicular fluid exposure further increasing abundance of interferon-stimulated gene (ISG) transcripts, including the ubiquitin-like protein ISG15 and other ISGylation pathway members. Both NFκB and type I interferon signaling are upregulated by stimulation of cGAS-STING or MDA5 and RIGI pattern recognition receptors. Since some pattern recognition receptors and their signal transduction pathway members are ISGylated, we tested the impact of ISG15 and ISGylation on interferon regulatory factor 3 (IRF3) and NFκB signaling through cGAS-STING or RIGI and MDA5 activation. Expression of ISG15 or UBA7, the E1-like ISG15-activating enzyme, in immortalized FTE cells was disrupted by CRISPR gene editing. Activation of IRF3 by RIGI or MDA5 but not cGAS-STING was attenuated by loss of either ISG15 or UBA7 and this was reflected by a similar effect on NFκB activation and downstream targets. Loss of ISGylation decreased levels of both MDA5 and RIGI, with knockdown of RIGI but not MDA5, decreasing IRF3 and NFκB activation in parental cells. These finding indicate that ISGylation enhances the ability of dsRNA to activate cytokine release and proinflammatory signaling. Further work to explore ISGylation as a target for prevention of high-grade serous tubo-ovarian cancer in BRCA1 mutation carriers is warranted.
Collapse
Affiliation(s)
- Vidushi Madaan
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | - Alexandra Kollara
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada
| | - David Spaner
- Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Theodore J Brown
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
7
|
Li S, Hao L, Li N, Hu X, Yan H, Dai E, Shi X. Targeting the Hippo/YAP1 signaling pathway in hepatocellular carcinoma: From mechanisms to therapeutic drugs (Review). Int J Oncol 2024; 65:88. [PMID: 39092548 DOI: 10.3892/ijo.2024.5676] [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: 06/04/2024] [Accepted: 07/15/2024] [Indexed: 08/04/2024] Open
Abstract
The Hippo signaling pathway plays a pivotal role in regulating cell growth and organ size. Its regulatory effects on hepatocellular carcinoma (HCC) encompass diverse aspects, including cell proliferation, invasion and metastasis, tumor drug resistance, metabolic reprogramming, immunomodulatory effects and autophagy. Yes‑associated protein 1 (YAP1), a potent transcriptional coactivator and a major downstream target tightly controlled by the Hippo pathway, is influenced by various molecules and pathways. The expression of YAP1 in different cell types within the liver tumor microenvironment exerts varying effects on tumor outcomes, warranting careful consideration. Therefore, research on YAP1‑targeted therapies merits attention. This review discusses the composition and regulation mechanism of the Hippo/YAP1 signaling pathway and its relationship with HCC, offering insights for future research and cancer prevention strategies.
Collapse
Affiliation(s)
- Shenghao Li
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Liyuan Hao
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Na Li
- Clinical Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, P.R. China
| | - Xiaoyu Hu
- Department of Infectious Diseases, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610072, P.R. China
| | - Huimin Yan
- Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050024, P.R. China
| | - Erhei Dai
- Clinical Research Center, Shijiazhuang Fifth Hospital, Shijiazhuang, Hebei 050024, P.R. China
| | - Xinli Shi
- Center of Experimental Management, Shanxi University of Chinese Medicine, Jinzhong, Shanxi 030619, P.R. China
| |
Collapse
|
|
8
|
Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 84] [Impact Index Per Article: 84.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
Collapse
Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
| |
Collapse
|
|
9
|
Xue Y, Ruan Y, Wang Y, Xiao P, Xu J. Signaling pathways in liver cancer: pathogenesis and targeted therapy. MOLECULAR BIOMEDICINE 2024; 5:20. [PMID: 38816668 PMCID: PMC11139849 DOI: 10.1186/s43556-024-00184-0] [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: 01/04/2024] [Accepted: 04/23/2024] [Indexed: 06/01/2024] Open
Abstract
Liver cancer remains one of the most prevalent malignancies worldwide with high incidence and mortality rates. Due to its subtle onset, liver cancer is commonly diagnosed at a late stage when surgical interventions are no longer feasible. This situation highlights the critical role of systemic treatments, including targeted therapies, in bettering patient outcomes. Despite numerous studies on the mechanisms underlying liver cancer, tyrosine kinase inhibitors (TKIs) are the only widely used clinical inhibitors, represented by sorafenib, whose clinical application is greatly limited by the phenomenon of drug resistance. Here we show an in-depth discussion of the signaling pathways frequently implicated in liver cancer pathogenesis and the inhibitors targeting these pathways under investigation or already in use in the management of advanced liver cancer. We elucidate the oncogenic roles of these pathways in liver cancer especially hepatocellular carcinoma (HCC), as well as the current state of research on inhibitors respectively. Given that TKIs represent the sole class of targeted therapeutics for liver cancer employed in clinical practice, we have particularly focused on TKIs and the mechanisms of the commonly encountered phenomena of its resistance during HCC treatment. This necessitates the imperative development of innovative targeted strategies and the urgency of overcoming the existing limitations. This review endeavors to shed light on the utilization of targeted therapy in advanced liver cancer, with a vision to improve the unsatisfactory prognostic outlook for those patients.
Collapse
Affiliation(s)
- Yangtao Xue
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yeling Ruan
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Yali Wang
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China
- Zhejiang University Cancer Center, Hangzhou, 310058, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China
| | - Peng Xiao
- Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
| | - Junjie Xu
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
- National Engineering Research Center of Innovation and Application of Minimally Invasive Instruments, Hangzhou, 310016, China.
- Zhejiang Minimal Invasive Diagnosis and Treatment Technology Research Center of Severe Hepatobiliary Disease, Zhejiang Research and Development Engineering Laboratory of Minimally Invasive Technology and Equipment, Hangzhou, 310016, China.
- Zhejiang University Cancer Center, Hangzhou, 310058, China.
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, 311121, China.
| |
Collapse
|
|
10
|
Wang M, Meng J, Wang H, Hu H, Hong Y. Atractylodes macrocephala III suppresses EMT in cervical cancer by regulating IGF2BP3 through ETV5. J Cell Mol Med 2024; 28:e18081. [PMID: 38358034 PMCID: PMC10868144 DOI: 10.1111/jcmm.18081] [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: 07/04/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 02/16/2024] Open
Abstract
Atractylodes macrocephala III (ATL III), with anti-inflammatory and antitumor effects, is the main compound of Atractylodes macrocephala. Whether ATL III has an effect on cervical cancer and the specific mechanism are still unclear. Here, we investigated the effects of ATL III on cervical cancer cells at different concentrations and found that ATL III downregulates insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), which was found to be highly expressed in cervical cancer tissue by RNA-Seq. In this study, we found that ATL III promotes apoptosis and regulates epithelial-mesenchymal transition (EMT) in cervical cancer cells (HeLa and SiHa cells) and that IGF2BP3 is a common target gene of ATL III in HeLa and SiHa cells. The expression level of IGF2BP3 in cervical cancer cells was proportional to their migration and invasion abilities. This was verified by transfection of cells with a small interfering RNA and an IGF2BP3 overexpression plasmid. After ATL III treatment, the migration and invasion abilities of cervical cancer cells were obviously reduced, but these effects were attenuated after overexpression of IGF2BP3. In addition, the transcription factor IGF2BP3 was predicted by the JASPAR system. After intersection with our sequencing results, we verified the promotional effect of ETV5 (ETS translocation variant 5) on IGF2BP3 and found that ALT III inhibited ETV5. In general, our research showed that ATL III inhibits the migration and invasion of cervical cancer cells by regulating IGF2BP3 through ETV5.
Collapse
Affiliation(s)
- Meixia Wang
- Department of Gynecology and ObstetricsNanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese MedicineNanjingChina
- Department of Gynecology and ObstetricsWenzhou Hospital of Integrated Traditional Chinese and Western MedicineWenzhouChina
| | - Jingwen Meng
- Department of Gynecology and ObstetricsNanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing Medical UniversityNanjingChina
| | - Hongyun Wang
- Department of Gynecology and ObstetricsNanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical SchoolNanjingChina
| | - Huijuan Hu
- Department of Gynecology and ObstetricsWenzhou Hospital of Integrated Traditional Chinese and Western MedicineWenzhouChina
| | - Ying Hong
- Department of Gynecology and ObstetricsNanjing Drum Tower Hospital, Clinical College of Nanjing University of Chinese MedicineNanjingChina
| |
Collapse
|
|
11
|
Sun X, Ye G, Li J, Shou H, Bai G, Zhang J. Parkin regulates IGF2BP3 through ubiquitination in the tumourigenesis of cervical cancer. Clin Transl Med 2023; 13:e1457. [PMID: 37877353 PMCID: PMC10599278 DOI: 10.1002/ctm2.1457] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Revised: 10/02/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND Insulin-like growth Factor 2 mRNA-binding protein 3 (IGF2BP3) is a highly conserved RNA-binding protein and plays a critical role in regulating posttranscriptional modifications. METHODS Immunoprecipitation was used to examine the interaction of Parkin and IGF2BP3. Mass spectrometry was performed to identify the ubiquitination sites of IGF2BP3. RNA-immunoprecipitation was conducted to examine the target genes of IGF2BP3. Xenograft mouse model was constructed to determine the tumorigenesis of IGF2BP3. RESULTS IGF2BP3 expression is negatively correlated with Parkin expression in human cervical cancer cells and tissues. Parkin directly interacts with IGF2BP3, and overexpression of Parkin causes the proteasomal degradation of IGF2BP3, while knockdown of PARK2 increases the protein levels of IGF2BP3. Mechanistically, in vivo and in vitro ubiquitination assays demonstrated that Parkin is able to ubiquitinate IGF2BP3. Moreover, the ubiquitination site of IGF2BP3 was identified at K213 in the first KH domain of IGF2BP3. IGF2BP3 mutation results in the loss of its oncogenic function as an m6A reader, resulting in the inactivation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signalling pathways. In addition, IGF2BP3 mutation results in the attenuation of Parkin-mediated mitophagy, indicating its inverse role in regulating Parkin. Consequently, the tumourigenesis of cervical cancer is also inhibited by IGF2BP3 mutation. CONCLUSION IGF2BP3 is ubiquitinated and regulated by the E3 ubiquitin ligase Parkin in human cervical cancer and ubiquitination modification plays an important role in modulating IGF2BP3 function. Thus, understanding the role of IGF2BP3 in tumourigenesis could provide new insights into cervical cancer therapy.
Collapse
Affiliation(s)
- Xin Sun
- Department of Medical OncologyCancer CenterKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)HangzhouChina
| | - Guiqin Ye
- Basic Medical SciencesHangzhou Medical CollegeHangzhouChina
| | - Jiuzhou Li
- Department of NeurosurgeryBinzhou People's HospitalBinzhouChina
| | - Huafeng Shou
- Department of GynecologyZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)BinzhouChina
| | - Gongxun Bai
- Key Laboratory of Rare Earth Optoelectronic Materials and Devices of Zhejiang Province, College of Optical and Electronic TechnologyChina Jiliang UniversityHangzhouChina
| | - Jianbin Zhang
- Department of Medical OncologyCancer CenterKey Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang ProvinceZhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)HangzhouChina
| |
Collapse
|
|
12
|
Nakagawa C, Kadlera Nagaraj M, Hernandez JC, Uthay Kumar DB, Shukla V, Machida R, Schüttrumpf J, Sher L, Farci P, Mishra L, Tahara SM, Ou JHJ, Machida K. β-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy. Front Immunol 2023; 14:1204907. [PMID: 37744383 PMCID: PMC10516572 DOI: 10.3389/fimmu.2023.1204907] [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: 04/13/2023] [Accepted: 08/03/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Tumor-initiating cells (TICs) are rare, stem-like, and highly malignant. Although intravenous hepatitis B and C immunoglobulins have been used for HBV and HCV neutralization in patients, their tumor-inhibitory effects have not yet been examined. Hepatitis B immunoglobulin (HBIG) therapy is employed to reduce hepatocellular carcinoma (HCC) recurrence in patients after living donor liver transplantations (LDLT). Hypothesis We hypothesized that patient-derived intravenous immunoglobulin (IVIG) binding to HCC associated TICs will reduce self-renewal and cell viability driven by β-CATENIN-downstream pathways. β-CATENIN activity protected TICs from IVIG effects. Methods The effects of HBIG and HCIG binding to TICs were evaluated for cell viability and self-renewal. Results Inhibition of β-CATENIN pathway(s) augmented TIC susceptibility to HBIG- and HCIG-immunotherapy. HBV X protein (HBx) upregulates both β-CATENIN and NANOG expression. The co-expression of constitutively active β-CATENIN with NANOG promotes self-renewal ability and tumor-initiating ability of hepatoblasts. HBIG bound to HBV+ cells led to growth inhibition in a TIC subset that expressed hepatitis B surface antigen. The HBx protein transformed cells through β-CATENIN-inducible lncRNAs EGLN3-AS1 and lnc-β-CatM. Co-expression of constitutively active β-CATENIN with NANOG promoted self-renewal ability of TICs through EGLN3 induction. β-CATENIN-induced lncRNAs stabilized HIF2 to maintain self-renewal of TICs. Targeting of EGLN3-AS1 resulted in destabilization of EZH2-dependent β-CATENIN activity and synergized cell-killing of TICs by HBIG or HCIG immunotherapy. Discussion Taken together, WNT and stemness pathways induced HIF2 of TICs via cooperating lncRNAs resulting in resistance to cancer immunotherapy. Therefore, therapeutic use of IVIG may suppress tumor recurrence through inhibition of TICs.
Collapse
Affiliation(s)
- Chad Nakagawa
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Manjunatha Kadlera Nagaraj
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Juan Carlos Hernandez
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Dinesh Babu Uthay Kumar
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Vivek Shukla
- University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Risa Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | | | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA, United States
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Lopa Mishra
- University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Stanley M. Tahara
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
| | - Keigo Machida
- Department of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, United States
- Southern California Research Center for Alcoholic Liver Disease and Pancreatic Disease (ALPD) and Cirrhosis, Los Angeles, CA, United States
| |
Collapse
|
|
13
|
Wang Q, Xiong F, Wu G, Wang D, Liu W, Chen J, Qi Y, Wang B, Chen Y. SMAD Proteins in TGF-β Signalling Pathway in Cancer: Regulatory Mechanisms and Clinical Applications. Diagnostics (Basel) 2023; 13:2769. [PMID: 37685308 PMCID: PMC10487229 DOI: 10.3390/diagnostics13172769] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/17/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Suppressor of mother against decapentaplegic (SMAD) family proteins are central to one of the most versatile cytokine signalling pathways in metazoan biology, the transforming growth factor-β (TGF-β) pathway. The TGF-β pathway is widely known for its dual role in cancer progression as both an inhibitor of tumour cell growth and an inducer of tumour metastasis. This is mainly mediated through SMAD proteins and their cofactors or regulators. SMAD proteins act as transcription factors, regulating the transcription of a wide range of genes, and their rich post-translational modifications are influenced by a variety of regulators and cofactors. The complex role, mechanisms, and important functions of SMAD proteins in tumours are the hot topics in current oncology research. In this paper, we summarize the recent progress on the effects and mechanisms of SMAD proteins on tumour development, diagnosis, treatment and prognosis, and provide clues for subsequent research on SMAD proteins in tumours.
Collapse
Affiliation(s)
- Qi Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Fei Xiong
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Guanhua Wu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Da Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Wenzheng Liu
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Junsheng Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Yongqiang Qi
- Key Laboratory of Laparoscopic Technology of Zhejiang Province, Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China;
| | - Bing Wang
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| | - Yongjun Chen
- Department of Biliary-Pancreatic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China; (Q.W.); (F.X.); (G.W.); (D.W.); (W.L.); (J.C.); (B.W.)
| |
Collapse
|
|
14
|
Yeh DW, Liu C, Hernandez JC, Tahara SM, Tsukamoto H, Machida K. Polycomb repressive complex 2 binds and stabilizes NANOG to suppress differentiation-related genes to promote self-renewal. iScience 2023; 26:107035. [PMID: 37448562 PMCID: PMC10336160 DOI: 10.1016/j.isci.2023.107035] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/20/2023] [Accepted: 05/31/2023] [Indexed: 07/15/2023] Open
Abstract
The synergistic effect of alcohol and HCV mediated through TLR4 signaling transactivates NANOG, a pluripotency transcription factor important for the stemness of tumor-initiating stem-like cells (TICs). NANOG together with the PRC2 complex suppresses expression of oxidative phosphorylation (OXPHOS) genes to generate TICs. The phosphodegron sequence PEST domain of NANOG binds EED to stabilize NANOG protein by blocking E3 ligase recruitment and proteasome-dependent degradation, while the tryptophan-rich domain of NANOG binds EZH2 and SUZ12. Human ARID1A gene loss results in the resistance to combined FAO and PRC2 inhibition therapies due to reduction of mitochondrial ROS levels. CRISPR-Cas9-mediated ARID1A knockout and/or constitutively active CTNNB1 driver mutations promoted tumor development in humanized FRG HCC mouse models, in which use of an interface inhibitor antagonizing PRC2-NANOG binding and/or FAO inhibitor blocked tumor growth. Together, the PRC2-NANOG interaction becomes a new drug target for HCC via inducing differentiation-related genes, destabilizing NANOG protein, and suppressing NANOG activity.
Collapse
Affiliation(s)
- Da-Wei Yeh
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Cheng Liu
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology; University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA 90033, USA
| |
Collapse
|
|
15
|
Han X, Ji G, Wang N, Yi L, Mao Y, Deng J, Wu H, Ma S, Han J, Bu Y, Fang P, Liu J, Sun F, Song X. Comprehensive analysis of m 6A regulators characterized by the immune microenvironment in Duchenne muscular dystrophy. J Transl Med 2023; 21:459. [PMID: 37434186 DOI: 10.1186/s12967-023-04301-5] [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: 11/19/2022] [Accepted: 06/24/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is an X-linked, incurable, degenerative neuromuscular disease that is exacerbated by secondary inflammation. N6-methyladenosine (m6A), the most common base modification of RNA, has pleiotropic immunomodulatory effects in many diseases. However, the role of m6A modification in the immune microenvironment of DMD remains elusive. METHODS Our study retrospectively analyzed the expression data of 56 muscle tissues from DMD patients and 26 from non-muscular dystrophy individuals. Based on single sample gene set enrichment analysis, immune cells infiltration was identified and the result was validated by flow cytometry analysis and immunohistochemical staining. Then, we described the features of genetic variation in 26 m6A regulators and explored their relationship with the immune mircoenvironment of DMD patients through a series of bioinformatical analysis. At last, we determined subtypes of DMD patients by unsupervised clustering analysis and characterized the molecular and immune characteristics in different subgroups. RESULTS DMD patients have a sophisticated immune microenvironment that is significantly different from non-DMD controls. Numerous m6A regulators were aberrantly expressed in the muscle tissues of DMD and inversely related to most muscle-infiltrating immune cell types and immune response-related signaling pathways. A diagnostic model involving seven m6A regulators was established using LASSO. Furthermore, we determined three m6A modification patterns (cluster A/B/C) with distinct immune microenvironmental characteristics. CONCLUSION In summary, our study demonstrated that m6A regulators are intimately linked to the immune microenvironment of muscle tissues in DMD. These findings may facilitate a better understanding of the immunomodulatory mechanisms in DMD and provide novel strategies for the treatment.
Collapse
Affiliation(s)
- Xu Han
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Guang Ji
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Ning Wang
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Le Yi
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Yafei Mao
- Department of Laboratory Medicine, The First Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China
| | - Jinliang Deng
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Hongran Wu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Shaojuan Ma
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Jingzhe Han
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Yi Bu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Pingping Fang
- Department of Neurology, Handan Central Hospital, Handan, 050000, Hebei, People's Republic of China
| | - Juyi Liu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Fanzhe Sun
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China
| | - Xueqin Song
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
- The Key Laboratory of Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang, 050000, Hebei, People's Republic of China.
- Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China.
| |
Collapse
|
|
16
|
Luo W, Li Y, Zeng Y, Li Y, Cheng M, Zhang C, Li F, Wu Y, Huang C, Yang X, Kremerskothen J, Zhang J, Zhang C, Tu S, Li Z, Luo Z, Lin Z, Yan X. Tea domain transcription factor TEAD4 mitigates TGF-β signaling and hepatocellular carcinoma progression independently of YAP. J Mol Cell Biol 2023; 15:mjad010. [PMID: 36806855 PMCID: PMC10446140 DOI: 10.1093/jmcb/mjad010] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 02/12/2023] [Accepted: 02/17/2023] [Indexed: 02/23/2023] Open
Abstract
Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yes-associated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforming growth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 plays a YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and target gene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenograft tumor growth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically, TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3 to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent of YAP, as impairing the TEAD4-YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAP-independent manner.
Collapse
Affiliation(s)
- Weicheng Luo
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Yi Li
- Department of Rheumatology and Clinical Immunology, Jiangxi Provincial People’s Hospital, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, China
| | - Yi Zeng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Yining Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Minzhang Cheng
- Center for Experimental Medicine, The First Affiliated Hospital of Nanchang University, Nanchang 330006, China
| | - Cheng Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Fei Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Yiqing Wu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Chunhong Huang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Xiaolong Yang
- Department of Pathology and Molecular Medicine, Queen’s University, Kingston, ON K7L 3N6, Canada
| | - Joachim Kremerskothen
- Department of Nephrology, Hypertension and Rheumatology, University Hospital Münster, Münster 48149, Germany
| | - Jianmin Zhang
- Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, Buffalo, NY 14203, USA
| | - Chunbo Zhang
- School of Pharmacy, Nanchang
University Jiangxi Medical College, Nanchang 330008, China
| | - Shuo Tu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
| | - Zhihua Li
- Key Laboratory of Breast Diseases of Jiangxi Province, Nanchang People’s Hospital, Nanchang 330025, China
| | - Zhijun Luo
- Department of Pathology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330006, China
| | - Zhenghong Lin
- School of Life Sciences, Chongqing University, Chongqing 405200, China
| | - Xiaohua Yan
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Nanchang University Jiangxi Medical College, Nanchang 330031, China
- Key Laboratory of Breast Diseases of Jiangxi Province, Nanchang People’s Hospital, Nanchang 330025, China
| |
Collapse
|
|
17
|
Qadir J, Wen SY, Yuan H, Yang BB. CircRNAs regulate the crosstalk between inflammation and tumorigenesis: The bilateral association and molecular mechanisms. Mol Ther 2023; 31:1514-1532. [PMID: 36518080 PMCID: PMC10278049 DOI: 10.1016/j.ymthe.2022.12.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/16/2022] [Accepted: 12/09/2022] [Indexed: 12/15/2022] Open
Abstract
Inflammation, a hallmark of cancer, has been associated with tumor progression, transition into malignant phenotype and efficacy of the chemotherapeutic agents in cancer. Chronic inflammation provides a favorable environment for tumorigenesis by inducing immunosuppression, whereas acute inflammation prompts tumor suppression by generating anti-tumor immune responses. Inflammatory factors derived from interstitial cells or tumor cells can stimulate cell proliferation and survival by modulating oncogenes and/or tumor suppressors. Recently, a new class of RNAs, i.e., circular RNAs (circRNAs), has been implicated in inflammatory diseases. Although there are reports on circRNAs imparting functions in inflammatory insults, whether these circularized transcripts hold the potential to regulate inflammation-induced cancer or tumor-related inflammation, and modulate the interactions between tumor microenvironment (TME) and the inflammatory stromal/immune cells, awaits further elucidation. Contextually, the current review describes the molecular association between inflammation and cancer, and spotlights the regulatory mechanisms by which circRNAs can moderate TME in response to inflammatory signals/triggers. We also present comprehensive information about the immune cell(s)-specific expression and functions of the circRNAs in TME, modulation of inflammatory signaling pathways to drive tumorigenesis, and their plausible roles in inflammasomes and tumor development. Moreover, the therapeutic potential of these circRNAs in harnessing inflammatory responses in cancer is also discussed.
Collapse
Affiliation(s)
- Javeria Qadir
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Biosciences, COMSATS University Islamabad, Islamabad, Pakistan; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Shuo-Yang Wen
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Hui Yuan
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Burton B Yang
- Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
18
|
Chen C, Hernandez JC, Uthaya Kumar DB, Machida T, Tahara SM, El‐Khoueiry A, Li M, Punj V, Swaminathan SK, Kirtane A, Chen Y, Panyam J, Machida K. Profiling of Circulating Tumor Cells for Screening of Selective Inhibitors of Tumor-Initiating Stem-Like Cells. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2206812. [PMID: 36949364 PMCID: PMC10190641 DOI: 10.1002/advs.202206812] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 01/20/2023] [Indexed: 05/18/2023]
Abstract
A critical barrier to effective cancer therapy is the improvement of drug selectivity, toxicity, and reduced recurrence of tumors expanded from tumor-initiating stem-like cells (TICs). The aim is to identify circulating tumor cell (CTC)-biomarkers and to identify an effective combination of TIC-specific, repurposed federal drug administration (FDA)-approved drugs. Three different types of high-throughput screens targeting the TIC population are employed: these include a CD133 (+) cell viability screen, a NANOG expression screen, and a drug combination screen. When combined in a refined secondary screening approach that targets Nanog expression with the same FDA-approved drug library, histone deacetylase (HDAC) inhibitor(s) combined with all-trans retinoic acid (ATRA) demonstrate the highest efficacy for inhibition of TIC growth in vitro and in vivo. Addition of immune checkpoint inhibitor further decreases recurrence and extends PDX mouse survival. RNA-seq analysis of TICs reveals that combined drug treatment reduces many Toll-like receptors (TLR) and stemness genes through repression of the lncRNA MIR22HG. This downregulation induces PTEN and TET2, leading to loss of the self-renewal property of TICs. Thus, CTC biomarker analysis would predict the prognosis and therapy response to this drug combination. In general, biomarker-guided stratification of HCC patients and TIC-targeted therapy should eradicate TICs to extend HCC patient survival.
Collapse
Affiliation(s)
- Chia‐Lin Chen
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
- Present address:
Department of Life Sciences & Institute of Genome SciencesNational Yang Ming Chiao Tung University110TaipeiTaiwan
| | - Juan Carlos Hernandez
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
- California State UniversityChannel IslandsCamarilloCAUSA
| | - Dinesh Babu Uthaya Kumar
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
| | - Tatsuya Machida
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
| | - Anthony El‐Khoueiry
- Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaKeck School of MedicineLos AngelesCA90033USA
| | - Meng Li
- Norris Medical Library2003 Zonal AveLos AngelesCA90089USA
| | - Vasu Punj
- Department of MedicineUniversity of Southern California Keck School of Medicine and Norris Comprehensive Cancer CenterLos AngelesCA90089USA
| | | | - Ameya Kirtane
- Department of PharmaceuticsUniversity of MinnesotaMinneapolisMN55455USA
| | - Yibu Chen
- Norris Medical Library2003 Zonal AveLos AngelesCA90089USA
| | - Jayanth Panyam
- Department of PharmaceuticsUniversity of MinnesotaMinneapolisMN55455USA
| | - Keigo Machida
- Departments of Molecular Microbiology and ImmunologyUniversity of Southern CaliforniaLos AngelesCA90033USA
- Southern California Research Center for ALPD and CirrhosisLos AngelesCA90033USA
| |
Collapse
|
|
19
|
Foglia B, Beltrà M, Sutti S, Cannito S. Metabolic Reprogramming of HCC: A New Microenvironment for Immune Responses. Int J Mol Sci 2023; 24:7463. [PMID: 37108625 PMCID: PMC10138633 DOI: 10.3390/ijms24087463] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatocellular carcinoma is the most common primary liver cancer, ranking third among the leading causes of cancer-related mortality worldwide and whose incidence varies according to geographical area and ethnicity. Metabolic rewiring was recently introduced as an emerging hallmark able to affect tumor progression by modulating cancer cell behavior and immune responses. This review focuses on the recent studies examining HCC's metabolic traits, with particular reference to the alterations of glucose, fatty acid and amino acid metabolism, the three major metabolic changes that have gained attention in the field of HCC. After delivering a panoramic picture of the peculiar immune landscape of HCC, this review will also discuss how the metabolic reprogramming of liver cancer cells can affect, directly or indirectly, the microenvironment and the function of the different immune cell populations, eventually favoring the tumor escape from immunosurveillance.
Collapse
Affiliation(s)
- Beatrice Foglia
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
| | - Marc Beltrà
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
- Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain
| | - Salvatore Sutti
- Department of Health Sciences, Interdisciplinary Research Center for Autoimmune Diseases, University of East Piedmont, 28100 Novara, Italy
| | - Stefania Cannito
- Unit of Experimental Medicine and Clinical Pathology, Department of Clinical and Biological Sciences, University of Torino, 10125 Torino, Italy
| |
Collapse
|
|
20
|
Hernandez JC, Chen CL, Machida T, Uthaya Kumar DB, Tahara SM, Montana J, Sher L, Liang J, Jung JU, Tsukamoto H, Machida K. LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells. iScience 2023; 26:106254. [PMID: 36949755 PMCID: PMC10025994 DOI: 10.1016/j.isci.2023.106254] [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: 01/03/2020] [Revised: 01/09/2022] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 (caTLR4) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC.
Collapse
Affiliation(s)
- Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA
| | - Chia-Lin Chen
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan
| | - Tatsuya Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Dinesh Babu Uthaya Kumar
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jared Montana
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
| | | | - Jae U. Jung
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
| |
Collapse
|
|
21
|
Matthiesen S, Christiansen B, Jahnke R, Zaeck LM, Karger A, Finke S, Franzke K, Knittler MR. TGF-β/IFN-γ Antagonism in Subversion and Self-Defense of Phase II Coxiella burnetii -Infected Dendritic Cells. Infect Immun 2023; 91:e0032322. [PMID: 36688662 PMCID: PMC9933720 DOI: 10.1128/iai.00323-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 12/20/2022] [Indexed: 01/24/2023] Open
Abstract
Dendritic cells (DCs) belong to the first line of innate defense and come into early contact with invading pathogens, including the zoonotic bacterium Coxiella burnetii, the causative agent of Q fever. However, the pathogen-host cell interactions in C. burnetii-infected DCs, particularly the role of mechanisms of immune subversion beyond virulent phase I lipopolysaccharide (LPS), as well as the contribution of cellular self-defense strategies, are not understood. Using phase II Coxiella-infected DCs, we show that impairment of DC maturation and MHC I downregulation is caused by autocrine release and action of immunosuppressive transforming growth factor-β (TGF-β). Our study demonstrates that IFN-γ reverses TGF-β impairment of maturation/MHC I presentation in infected DCs and activates bacterial elimination, predominantly by inducing iNOS/NO. Induced NO synthesis strongly affects bacterial growth and infectivity. Moreover, our studies hint that Coxiella-infected DCs might be able to protect themselves from mitotoxic NO by switching from oxidative phosphorylation to glycolysis, thus ensuring survival in self-defense against C. burnetii. Our results provide new insights into DC subversion by Coxiella and the IFN-γ-mediated targeting of C. burnetii during early steps in the innate immune response.
Collapse
Affiliation(s)
- Svea Matthiesen
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Bahne Christiansen
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Rico Jahnke
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Luca M. Zaeck
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Axel Karger
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Stefan Finke
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Kati Franzke
- Institute of Infectology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| | - Michael R. Knittler
- Institute of Immunology, Friedrich-Loeffler-Institut, Federal Research Institute of Animal Health, Isle of Riems, Germany
| |
Collapse
|
|
22
|
Jeng KS, Chang CF, Sheen IS, Jeng CJ, Wang CH. Cellular and Molecular Biology of Cancer Stem Cells of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:1417. [PMID: 36674932 PMCID: PMC9861908 DOI: 10.3390/ijms24021417] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/03/2023] [Accepted: 01/04/2023] [Indexed: 01/12/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death globally. The cancer stem cells (CSCs) of HCC are responsible for tumor growth, invasion, metastasis, recurrence, chemoresistance, target therapy resistance and radioresistance. The reported main surface markers used to identify liver CSCs include epithelial cell adhesion/activating molecule (EpCAM), cluster differentiation 90 (CD90), CD44 and CD133. The main molecular signaling pathways include the Wnt/β-catenin, transforming growth factors-β (TGF-β), sonic hedgehog (SHH), PI3K/Akt/mTOR and Notch. Patients with EpCAM-positive alpha-fetoprotein (AFP)-positive HCC are usually young but have advanced tumor-node-metastasis (TNM) stages. CD90-positive HCCs are usually poorly differentiated with worse prognosis. Those with CD44-positive HCC cells develop early metastases. Those with CD133 expression have a higher recurrence rate and a shorter overall survival. The Wnt/β-catenin signaling pathway triggers angiogenesis, tumor infiltration and metastasis through the enhancement of angiogenic factors. All CD133+ liver CSCs, CD133+/EpCAM+ liver CSCs and CD44+ liver CSCs contribute to sorafenib resistance. SHH signaling could protect HCC cells against ionizing radiation in an autocrine manner. Reducing the CSC population of HCC is crucial for the improvement of the therapy of advanced HCC. However, targeting CSCs of HCC is still challenging.
Collapse
Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - Chiung-Fang Chang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| | - I-Shyang Sheen
- Department of Hepato Gastroenterology, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan
| | - Chi-Juei Jeng
- Postgraduate of Institute of Medicine, National Taiwan University, Taipei 10617, Taiwan
| | - Chih-Hsuan Wang
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan
| |
Collapse
|
|
23
|
Kwan SY, Slayden AN, Coronado AR, Marquez RC, Chen H, Wei P, Savage MI, Vornik LA, Fox JT, Sei S, Liang D, Stevenson HL, Wilkerson GK, Gagea M, Brown PH, Beretta L. Treatment Strategies and Mechanisms Associated with the Prevention of NASH-Associated HCC by a Toll-like Receptor 4 Inhibitor. Cancer Prev Res (Phila) 2023; 16:17-28. [PMID: 36162136 PMCID: PMC9812917 DOI: 10.1158/1940-6207.capr-22-0332] [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: 07/13/2022] [Revised: 09/08/2022] [Accepted: 09/22/2022] [Indexed: 01/12/2023]
Abstract
We evaluated the cancer preventive efficacy of TAK-242, an inhibitor of Toll-like receptor 4 (TLR4), in a mouse model of hepatocellular carcinoma (HCC) occurring in the context of nonalcoholic steatohepatitis (NASH). We also assessed the cellular events associated with the preventive treatment efficacy. We tested oral administration of TAK-242, at clinically relevant but toxicity-reducing doses and scheduling, in mice with hepatocyte-specific deletion of Pten (HepPten-). The optimal dose and oral gavage formulation of TAK-242 were determined to be 30 mg/kg in 5% DMSO in 30% 2-hydroxypropyl-β-cyclodextrin. Daily oral administration of 30 mg/kg TAK-242 over 18 weeks was well tolerated and resulted in reduced development of tumors (lesions > 7.5 mm3) in HepPten- mice. This effect was accompanied by reduced macrovesicular steatosis and serum levels of alanine aminotransferase. In addition, 30 mg/kg TAK-242 daily treatment of small preexisting adenomas (lesions < 7.5 mm3) over 18 weeks, significantly reduced their progression to HCC. RNA sequencing identified 220 hepatic genes significantly altered upon TAK-242 treatment, that significantly correlated with tumor burden. Finally, cell deconvolution analysis revealed that TAK-242 treatment resulted in reduced hepatic populations of endothelial cells and myeloid-derived immune cells (Kupffer cells, Siglec-H high dendritic cells, and neutrophilic granule protein high neutrophils), while the proportion of mt-Nd4 high hepatocytes significantly increased, suggesting a decrease in hepatic inflammation and concomitant increase in mitochondrial function and oxidative phosphorylation upon TLR4 inhibition. In conclusion, this study identified treatment strategies and novel molecular and cellular mechanisms associated with the prevention of HCC in the context of NASH that merit further investigations. PREVENTION RELEVANCE Means to prevent development of HCC or progression of small adenomas to HCC in patients with NASH are urgently needed to reduce the growing mortality due to HCC. We characterized the chemopreventive effect of oral administration of the TLR4 inhibitor TAK-242 in a model of NASH-associated HCC.
Collapse
Affiliation(s)
- Suet-Ying Kwan
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Alyssa N. Slayden
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Aubrey R. Coronado
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Rosamaria C. Marquez
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Huiqin Chen
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Peng Wei
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Michelle I. Savage
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lana A. Vornik
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jennifer T. Fox
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
| | - Shizuko Sei
- Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland, USA
| | - Dong Liang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas, USA
| | - Heather L. Stevenson
- Department of Pathology, The University of Texas Medical Branch, Galveston, Texas, USA
| | - Gregory K. Wilkerson
- Keeling Center for Comparative Medicine and Research, University of Texas, MD Anderson Cancer Center, Bastrop, Texas, USA
| | - Mihai Gagea
- Department of Veterinary Medicine & Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Powel H. Brown
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| |
Collapse
|
|
24
|
Li J, Si SJ, Wu X, Zhang ZH, Li C, Tao YQ, Yang PK, Li DH, Li ZJ, Li GX, Liu XJ, Tian YD, Kang XT. CircEML1 facilitates the steroid synthesis in follicular granulosa cells of chicken through sponging gga-miR-449a to release IGF2BP3 expression. Genomics 2023; 115:110540. [PMID: 36563917 DOI: 10.1016/j.ygeno.2022.110540] [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: 09/14/2022] [Revised: 11/18/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Non-coding RNAs (ncRNAs) induced competing endogenous RNAs (ceRNA) play crucial roles in various biological process by regulating target gene expression. However, the studies of ceRNA networks in the regulation of ovarian ovulation processing of chicken remains deficient compared to that in mammals. Our present study revealed that circEML1 was differential expressed in hen's ovarian tissues at different ages (15 W/20 W/30 W/68 W) and identified as a loop structure from EML1 pre-mRNA, which promoted the expressions of CYP19A1/StAR and E2/P4 secretion in follicular granulosa cells (GCs). Furthermore, circEML1 could serve as a sponge of gga-miR-449a and also found that IGF2BP3 was targeted by gga-miR-449a to co-participate in the steroidogenesis, which possibly act the regulatory role via mTOR/p38MAPK pathways. Meanwhile, in the rescue experiment, gga-miR-449a could reverse the promoting role of circEML1 to IGF2BP3 and steroidogenesis. Eventually, this study suggested that circEML1/gga-miR-449a/IGF2BP3 axis exerted an important role in the steroidogenesis in GCs of chicken.
Collapse
Affiliation(s)
- Jing Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Su-Jin Si
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Xing Wu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Zi-Hao Zhang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Chong Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Yi-Qing Tao
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Peng-Kun Yang
- Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China
| | - Dong-Hua Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Zhuan-Jian Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Guo-Xi Li
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Xiao-Jun Liu
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China
| | - Ya-Dong Tian
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China.
| | - Xiang-Tao Kang
- College of Animal Science and Technology, Henan Agricultural University, Zhengzhou 450046, China; Henan Key laboratory for innovation and utilization of chicken germplasm resources, Zhengzhou 450046, China.
| |
Collapse
|
|
25
|
Da BL, Suchman KI, Lau L, Rabiee A, He AR, Shetty K, Yu H, Wong LL, Amdur RL, Crawford JM, Fox SS, Grimaldi GM, Shah PK, Weinstein J, Bernstein D, Satapathy SK, Chambwe N, Xiang X, Mishra L. Pathogenesis to management of hepatocellular carcinoma. Genes Cancer 2022; 13:72-87. [PMID: 36533190 PMCID: PMC9746873 DOI: 10.18632/genesandcancer.226] [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: 09/07/2022] [Accepted: 11/17/2022] [Indexed: 12/15/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.
Collapse
Affiliation(s)
- Ben L. Da
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Kelly I. Suchman
- Department of Internal Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Lawrence Lau
- Department of Surgery, North Shore University Hospital, Northwell Health, Manhasset, NY 11030, USA
| | - Atoosa Rabiee
- Department of Gastroenterology and Hepatology, VA Medical Center, Washington, DC 20422, USA
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA
| | - Kirti Shetty
- Division of Gastroenterology and Hepatology, University of Maryland, Baltimore, MD 21201, USA
| | - Herbert Yu
- Department of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813-5516, USA
| | - Linda L. Wong
- Department of Surgery, University of Hawaii, Honolulu, HI 96813-5516, USA
| | - Richard L. Amdur
- Quantitative Intelligence, The Institutes for Health Systems Science and Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 10022, USA
| | - James M. Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Sharon S. Fox
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Gregory M. Grimaldi
- Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Priya K. Shah
- Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - Jonathan Weinstein
- Division of Vascular and Interventional Radiology, Department of Radiology, Northwell Health, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY 11030, USA
| | - David Bernstein
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Sanjaya K. Satapathy
- Department of Internal Medicine, Division of Hepatology, Sandra Atlas Bass Center for Liver Diseases and Transplantation, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health, Manhasset, NY 11030, USA
| | - Nyasha Chambwe
- The Institute of Molecular Medicine, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research and Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, NY 11030, USA
| |
Collapse
|
|
26
|
Cancer Stem Cells in Hepatocellular Carcinoma: Intrinsic and Extrinsic Molecular Mechanisms in Stemness Regulation. Int J Mol Sci 2022; 23:ijms232012327. [PMID: 36293184 PMCID: PMC9604119 DOI: 10.3390/ijms232012327] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/18/2022] [Accepted: 10/04/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) remains the most predominant type of liver cancer with an extremely poor prognosis due to its late diagnosis and high recurrence rate. One of the culprits for HCC recurrence and metastasis is the existence of cancer stem cells (CSCs), which are a small subset of cancer cells possessing robust stem cell properties within tumors. CSCs play crucial roles in tumor heterogeneity constitution, tumorigenesis, tumor relapse, metastasis, and resistance to anti-cancer therapies. Elucidation of how these CSCs maintain their stemness features is essential for the development of CSCs-based therapy. In this review, we summarize the present knowledge of intrinsic molecules and signaling pathways involved in hepatic CSCs, especially the CSC surface markers and associated signaling in regulating the stemness characteristics and the heterogeneous subpopulations within the CSC pool. In addition, we recapitulate the effects of crucial extrinsic cellular components in the tumor microenvironment, including stromal cells and immune cells, on the modulation of hepatic CSCs. Finally, we synopsize the currently valuable CSCs-targeted therapy strategies based on intervention in these intrinsic and extrinsic molecular mechanisms, in the hope of shedding light on better clinical management of HCC patients.
Collapse
|
|
27
|
Tu T, Alba MM, Datta AA, Hong H, Hua B, Jia Y, Khan J, Nguyen P, Niu X, Pammidimukkala P, Slarve I, Tang Q, Xu C, Zhou Y, Stiles BL. Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis. Front Oncol 2022; 12:958696. [PMID: 36276076 PMCID: PMC9581256 DOI: 10.3389/fonc.2022.958696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 08/17/2022] [Indexed: 12/02/2022] Open
Abstract
Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.
Collapse
Affiliation(s)
- Taojian Tu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Aditi A. Datta
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Handan Hong
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Jared Khan
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Phillip Nguyen
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Xiatoeng Niu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Pranav Pammidimukkala
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Qi Tang
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Chenxi Xu
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Bangyan L. Stiles,
| |
Collapse
|
|
28
|
Ballout F, Lu H, Chen L, Sriramajayam K, Que J, Meng Z, Wang TC, Giordano S, Zaika A, McDonald O, Peng D, El-Rifai W. APE1 redox function is required for activation of Yes-associated protein 1 under reflux conditions in Barrett's-associated esophageal adenocarcinomas. J Exp Clin Cancer Res 2022; 41:264. [PMID: 36045416 PMCID: PMC9434868 DOI: 10.1186/s13046-022-02472-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/22/2022] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Esophageal adenocarcinoma (EAC) is characterized by poor prognosis and low survival rate. Chronic gastroesophageal reflux disease (GERD) is the main risk factor for the development of Barrett's esophagus (BE), a preneoplastic metaplastic condition, and its progression to EAC. Yes-associated protein 1 (YAP1) activation mediates stem-like properties under cellular stress. The role of acidic bile salts (ABS) in promoting YAP1 activation under reflux conditions remains unexplored. METHODS A combination of EAC cell lines, transgenic mice, and patient-derived xenografts were utilized in this study. mRNA expression and protein levels of APE1 and YAP1 were evaluated by qRT-PCR, western blot, and immunohistochemistry. YAP1 activation was confirmed by immunofluorescence staining and luciferase transcriptional activity reporter assay. The functional role and mechanism of regulation of YAP1 by APE1 was determined by sphere formation assay, siRNA mediated knockdown, redox-specific inhibition, and co-immunoprecipitation assays. RESULTS We showed that YAP1 signaling is activated in BE and EAC cells following exposure to ABS, the mimicry of reflux conditions in patients with GERD. This induction was consistent with APE1 upregulation in response to ABS. YAP1 activation was confirmed by its nuclear accumulation with corresponding up-regulation of YAP1 target genes. APE1 silencing inhibited YAP1 protein induction and reduced its nuclear expression and transcriptional activity, following ABS treatment. Further investigation revealed that APE1-redox-specific inhibition (E3330) or APE1 redox-deficient mutant (C65A) abrogated ABS-mediated YAP1 activation, indicating an APE1 redox-dependent mechanism. APE1 silencing or E3330 treatment reduced YAP1 protein levels and diminished the number and size of EAC spheroids. Mechanistically, we demonstrated that APE1 regulated YAP1 stability through interaction with β-TrCP ubiquitinase, whereas APE1-redox-specific inhibition induced YAP1 poly-ubiquitination promoting its degradation. CONCLUSION Our findings established a novel function of APE1 in EAC progression elucidating druggable molecular vulnerabilities via targeting APE1 or YAP1 for the treatment of EAC.
Collapse
Affiliation(s)
- Farah Ballout
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
| | - Heng Lu
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
| | - Lei Chen
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, P. R. China
| | - Kannappan Sriramajayam
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
| | - Jianwen Que
- Department of Medicine, Columbia University, New York, NY, 10027, USA
| | - Zhipeng Meng
- Department of Molecular and Cellular Pharmacology & Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Timothy C Wang
- Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Silvia Giordano
- Department of Oncology, University of Torino and Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, Italy
| | - Alexander Zaika
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
| | - Oliver McDonald
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, 33136, USA
| | - Dunfa Peng
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA
| | - Wael El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Med Science Bldg., 1600 NW 10th Ave, Room 4007, Miami, FL, 33136-1015, USA.
- Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA.
- Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA.
| |
Collapse
|
|
29
|
Wu H, Liu Y, Liao Z, Mo J, Zhang Q, Zhang B, Zhang L. The role of YAP1 in liver cancer stem cells: proven and potential mechanisms. Biomark Res 2022; 10:42. [PMID: 35672802 PMCID: PMC9171972 DOI: 10.1186/s40364-022-00387-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023] Open
Abstract
YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.
Collapse
Affiliation(s)
- Haofeng Wu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Zhibin Liao
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Jie Mo
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Qiaofeng Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Bixiang Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Lei Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, 030032, China.
| |
Collapse
|
|
30
|
Xiang X, Ohshiro K, Zaidi S, Yang X, Bhowmick K, Vegesna AK, Bernstein D, Crawford JM, Mishra B, Latham PS, Gough NR, Rao S, Mishra L. Impaired reciprocal regulation between SIRT6 and TGF-β signaling in fatty liver. FASEB J 2022; 36:e22335. [PMID: 35506565 PMCID: PMC11288617 DOI: 10.1096/fj.202101518r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 03/14/2022] [Accepted: 04/21/2022] [Indexed: 11/11/2022]
Abstract
Dysregulated transforming growth factor-beta (TGF-β) signaling contributes to fibrotic liver disease and hepatocellular cancer (HCC), both of which are associated with fatty liver disease. SIRT6 limits fibrosis by inhibiting TGF-β signaling through deacetylating SMAD2 and SMAD3 and limits lipogenesis by inhibiting SREBP1 and SREBP2 activity. Here, we showed that, compared to wild-type mice, high-fat diet-induced fatty liver is worse in TGF-β signaling-deficient mice (SPTBN1+/- ) and the mutant mice had reduced SIRT6 abundance in the liver. Therefore, we hypothesized that altered reciprocal regulation between TGF-β signaling and SIRT6 contributes to these liver pathologies. We found that deficiency in SMAD3 or SPTBN1 reduced SIRT6 mRNA and protein abundance and impaired TGF-β induction of SIRT6 transcripts, and that SMAD3 bound to the SIRT6 promoter, suggesting that an SMAD3-SPTBN1 pathway mediated the induction of SIRT6 in response to TGF-β. Overexpression of SIRT6 in HCC cells reduced the expression of TGF-β-induced genes, consistent with the suppressive role of SIRT6 on TGF-β signaling. Manipulation of SIRT6 abundance in HCC cells altered sterol regulatory element-binding protein (SREBP) activity and overexpression of SIRT6 reduced the amount of acetylated SPTBN1 and the abundance of both SMAD3 and SPTBN1. Furthermore, induction of SREBP target genes in response to SIRT6 overexpression was impaired in SPTBN1 heterozygous cells. Thus, we identified a regulatory loop between SIRT6 and SPTBN1 that represents a potential mechanism for susceptibility to fatty liver in the presence of dysfunctional TGF-β signaling.
Collapse
Affiliation(s)
- Xiyan Xiang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Kazufumi Ohshiro
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Sobia Zaidi
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Xiaochun Yang
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Krishanu Bhowmick
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
| | - Anil K. Vegesna
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - David Bernstein
- Division of Hepatology, Northwell Health and Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - James M Crawford
- Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, 11549, USA
| | - Bibhuti Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Department of Neurology, Northwell Health, Manhasset, NY, 11030, USA
| | - Patricia S. Latham
- Department of Pathology, George Washington University, Washington, DC, 20037, USA
| | - Nancy R. Gough
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Shuyun Rao
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Northwell Health, NY, 11030, USA
- Cold Spring Harbor Laboratory; Cold Spring Harbor, NY, 11724, USA
- Division of Gastroenterology, Department of Medicine, Northwell Health, NY, 11030, USA
- Department of Surgery, The George Washington University, Washington, DC, 20037, USA
| |
Collapse
|
|
31
|
Zhu RH, Dai FF, Yang DY, Liu SY, Zheng YJ, Wu ML, Deng ZM, Wang ZT, Zhang YW, Tan W, Li ZD, He J, Yang X, Hu M, Cheng YX. The Mechanism of Insulin-Like Growth Factor II mRNA-Binging Protein 3 Induce Decidualization and Maternal-Fetal Interface Cross Talk by TGF-β1 in Recurrent Spontaneous Abortion. Front Cell Dev Biol 2022; 10:862180. [PMID: 35465321 PMCID: PMC9023862 DOI: 10.3389/fcell.2022.862180] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/09/2022] [Indexed: 12/20/2022] Open
Abstract
Recurrent spontaneous abortion (RSA) is defined as the loss of two or more consecutive intrauterine pregnancies that are clinically established early in pregnancy. To date, the etiology and underlying mechanisms of RSA remain unclear. It is widely thought that the impairment of decidualization is inclined to induce subsequent pregnancy failure and leads to the dysregulation of extra-villous trophoblast invasion and proliferation through maternal–fetal cross talk. However, the mechanism of decidualization in RSA has yet to be understood. In our study, we demonstrate that decidual samples from RSA patients have significantly higher insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and lower TGF-β1 levels compared to healthy controls. In addition, the overexpression of IGF2BP3 in human endometrial stromal cells (hESCs) can lead to the impairment of decidualization in vitro-induced model and the abnormal cell cycle regulation. Furthermore, TGF-β1 and MMP9 levels were greatly increased after decidualization, whereas IGF2BP3 overexpression inhibited endometrial mesenchymal decidualization by downregulating TGF-β1, impeding maternal–fetal interface cytokine cross talk, and limiting the ability of trophoblast invasion. In conclusion, our investigation first demonstrates that abnormal elevation of IGF2BP3 in the pregnant endometrium leads to the impairment of decidualization and abnormal trophoblast invasion, thereby predisposing individuals to RSA.
Collapse
Affiliation(s)
- Rong-hui Zhu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Fang-fang Dai
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Dong-yong Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shi-yi Liu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ya-jing Zheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Ma-li Wu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhi-min Deng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zi-tao Wang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yu-wei Zhang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Wei Tan
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Zhi-dian Li
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Juan He
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiao Yang
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
- Department of Obstetrics and Gynecology, Peking University People’s Hospital, Beijing, China
- *Correspondence: Xiao Yang, ; Min Hu, ; Yan-xiang Cheng,
| | - Min Hu
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Xiao Yang, ; Min Hu, ; Yan-xiang Cheng,
| | - Yan-xiang Cheng
- Department of Obstetrics and Gynecology, Renmin Hospital of Wuhan University, Wuhan, China
- *Correspondence: Xiao Yang, ; Min Hu, ; Yan-xiang Cheng,
| |
Collapse
|
|
32
|
García-García M, Sánchez-Perales S, Jarabo P, Calvo E, Huyton T, Fu L, Ng SC, Sotodosos-Alonso L, Vázquez J, Casas-Tintó S, Görlich D, Echarri A, Del Pozo MA. Mechanical control of nuclear import by Importin-7 is regulated by its dominant cargo YAP. Nat Commun 2022; 13:1174. [PMID: 35246520 PMCID: PMC8897400 DOI: 10.1038/s41467-022-28693-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 01/19/2022] [Indexed: 12/31/2022] Open
Abstract
Mechanical forces regulate multiple essential pathways in the cell. The nuclear translocation of mechanoresponsive transcriptional regulators is an essential step for mechanotransduction. However, how mechanical forces regulate the nuclear import process is not understood. Here, we identify a highly mechanoresponsive nuclear transport receptor (NTR), Importin-7 (Imp7), that drives the nuclear import of YAP, a key regulator of mechanotransduction pathways. Unexpectedly, YAP governs the mechanoresponse of Imp7 by forming a YAP/Imp7 complex that responds to mechanical cues through the Hippo kinases MST1/2. Furthermore, YAP behaves as a dominant cargo of Imp7, restricting the Imp7 binding and the nuclear translocation of other Imp7 cargoes such as Smad3 and Erk2. Thus, the nuclear import process is an additional regulatory layer indirectly regulated by mechanical cues, which activate a preferential Imp7 cargo, YAP, which competes out other cargoes, resulting in signaling crosstalk. The translation of mechanical cues into gene expression changes is dependent on the nuclear import of mechanoresponsive transcriptional regulators. Here the authors identify that Importin-7 drives the nuclear import of one such regulator YAP while YAP then controls Importin-7 response to mechanical cues and restricts Importin-7 binding to other cargoes.
Collapse
Affiliation(s)
- María García-García
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Sara Sánchez-Perales
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Patricia Jarabo
- Instituto Cajal-CSIC, Avda. Doctor Arce, 37, 28002, Madrid, Spain
| | - Enrique Calvo
- Proteomics Unit. Area of Vascular Physiopathology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Trevor Huyton
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Liran Fu
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Sheung Chun Ng
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Laura Sotodosos-Alonso
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain
| | - Jesús Vázquez
- Proteomics Unit. Area of Vascular Physiopathology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.,CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | | | - Dirk Görlich
- Department of Cellular Logistics, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077, Göttingen, Germany
| | - Asier Echarri
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
| | - Miguel A Del Pozo
- Mechanoadaptation and Caveolae Biology Laboratory. Area of Cell & Developmental Biology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Calle Melchor Fernández Almagro, 3, 28029, Madrid, Spain.
| |
Collapse
|
|
33
|
Xu Y, Guo Z, Peng H, Guo L, Wang P. IGF2BP3 promotes cell metastasis and is associated with poor patient survival in nasopharyngeal carcinoma. J Cell Mol Med 2022; 26:410-421. [PMID: 34894048 PMCID: PMC8743660 DOI: 10.1111/jcmm.17093] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 11/08/2021] [Accepted: 11/17/2021] [Indexed: 11/29/2022] Open
Abstract
Metastasis contributes to treatment failure in nasopharyngeal carcinoma (NPC) patients. Our study aimed at elucidating the role of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) in NPC metastasis and the underlying mechanism involved. IGF2BP3 expression in NPC was determined by bioinformatics, quantitative polymerase chain reaction and immunohistochemistry analyses. The biological function of IGF2BP3 was investigated by using in vitro and in vivo studies. In this study, IGF2BP3 mRNA and protein levels were elevated in NPC tissues. In addition, IGF2BP3 exerted an oncogenic role by promoting epithelial-mesenchymal transition (EMT), thereby inducing NPC cell migration and invasion. Further studies revealed that IGF2BP3 regulated the expression of key regulators of EMT by activating AKT/mTOR signalling, thus stimulating NPC cell migration and invasion. Remarkably, targeting IGF2BP3 delayed NPC metastasis through attenuating p-AKT and vimentin expression and inducing E-cadherin expression in vivo. Moreover, IGF2BP3 protein levels positively correlated with distant metastasis after initial treatment. Importantly, IGF2BP3 expression served as an independent prognostic factor in predicting the overall survival and distant metastasis-free survival of NPC patients. This work identifies IGF2BP3 as a novel prognostic marker and a new target for NPC treatment.
Collapse
Affiliation(s)
- Yun Xu
- Departments of Radiation OncologyTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjinChina
- Fujian Medical University Cancer HospitalFujian Cancer HospitalFujianChina
| | - Zhoubo Guo
- Departments of Radiation OncologyTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjinChina
| | - Hewei Peng
- Department of Epidemiology and Health StatisticsFujian Provincial Key Laboratory of Environment Factors and CancerSchool of Public HealthFujian Medical UniversityFuzhouChina
| | - Lanyan Guo
- School of Medical Technology and EngineeringFujian Medical UniversityFuzhouChina
| | - Ping Wang
- Departments of Radiation OncologyTianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin’s Clinical Research Center for CancerTianjinChina
| |
Collapse
|
|
34
|
Zaidi S, Gough NR, Mishra L. Mechanisms and clinical significance of TGF-β in hepatocellular cancer progression. Adv Cancer Res 2022; 156:227-248. [DOI: 10.1016/bs.acr.2022.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
|
|
35
|
Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 280] [Impact Index Per Article: 93.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
Collapse
|
|
36
|
Wallis N, Oberman F, Shurrush K, Germain N, Greenwald G, Gershon T, Pearl T, Abis G, Singh V, Singh A, Sharma AK, Barr HM, Ramos A, Spiegelman VS, Yisraeli JK. Small molecule inhibitor of Igf2bp1 represses Kras and a pro-oncogenic phenotype in cancer cells. RNA Biol 2021; 19:26-43. [PMID: 34895045 PMCID: PMC8794255 DOI: 10.1080/15476286.2021.2010983] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 11/22/2021] [Indexed: 12/27/2022] Open
Abstract
Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).
Collapse
Affiliation(s)
- Nadav Wallis
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Froma Oberman
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Khriesto Shurrush
- The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Nicolas Germain
- The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Gila Greenwald
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Tehila Gershon
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Talia Pearl
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Giancarlo Abis
- Division of Biosciences, Institute of Structural and Molecular Biology, University College London, London, UK
| | - Vikash Singh
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Amandeep Singh
- Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA
| | - Arun K. Sharma
- Department of Pharmacology, Penn State Cancer Institute, Penn State College of Medicine, Hershey, PA, USA
| | - Haim M. Barr
- The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel
| | - Andres Ramos
- Division of Biosciences, Institute of Structural and Molecular Biology, University College London, London, UK
| | - Vladimir S. Spiegelman
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Joel K. Yisraeli
- Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| |
Collapse
|
|
37
|
Durślewicz J, Klimaszewska-Wiśniewska A, Jóźwicki J, Antosik P, Smolińska-Świtała M, Gagat M, Kowalewski A, Grzanka D. Prognostic Significance of TLR2, SMAD3 and Localization-dependent SATB1 in Stage I and II Non-Small-Cell Lung Cancer Patients. Cancer Control 2021; 28:10732748211056697. [PMID: 34818944 PMCID: PMC8640983 DOI: 10.1177/10732748211056697] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
This study aimed to explore the prognostic value of SATB1, SMAD3, and TLR2 expression in non-small-cell lung carcinoma patients with clinical stages I-II. To investigate, we evaluated immunohistochemical staining to each of these markers using tissue sections from 69 patients from our cohort and gene expression data for The Cancer Genome Atlas (TCGA) cohort. We found that, in our cohort, high expression levels of nuclear SATB1n and SMAD3 were independent prognostic markers for better overall survival (OS) in NSCLC patients. Interestingly, expression of cytoplasmic SATB1c exhibited a significant but inverse association with survival rate, and it was an independent predictor of unfavorable prognosis. Likewise, TLR2 was a negative outcome biomarker for NSCLC even when adjusting for covariates. Importantly, stratification of NSCLCs with respect to combined expression of the three biomarkers allowed us to identify subgroups of patients with the greatest difference in duration of survival. Specifically, expression profile of SATB1n-high/SMAD3high/TLR2low was associated with the best OS, and it was superior to each single protein alone in predicting patient prognosis. Furthermore, based on the TCGA dataset, we found that overexpression of SATB1 mRNA was significantly associated with better OS, whereas high mRNA levels of SMAD3 and TLR2 with poor OS. In conclusion, the present study identified a set of proteins that may play a significant role in predicting prognosis of NSCLC patients with clinical stages I-II.
Collapse
Affiliation(s)
- Justyna Durślewicz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Anna Klimaszewska-Wiśniewska
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Jakub Jóźwicki
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Marta Smolińska-Świtała
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Maciej Gagat
- Department of Histology and Embryology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| | - Adam Kowalewski
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland.,Department of Tumor Pathology and Pathomorphology, Oncology Centre, Prof Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, 49577Nicolaus Copernicus University, Toruń, Poland
| |
Collapse
|
|
38
|
Zhang Z, Zhang C, Luo Y, Wu P, Zhang G, Zeng Q, Wang L, Yang Z, Xue L, Zheng B, Zeng H, Tan F, Xue Q, Gao S, Sun N, He J. m 6A regulator expression profile predicts the prognosis, benefit of adjuvant chemotherapy, and response to anti-PD-1 immunotherapy in patients with small-cell lung cancer. BMC Med 2021; 19:284. [PMID: 34802443 PMCID: PMC8607595 DOI: 10.1186/s12916-021-02148-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/29/2021] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Small cell lung cancer (SCLC) is lethal and possesses limited therapeutic options. Platinum-based chemotherapy-with or without immune checkpoint inhibitors (anti-PDs)-is the current first-line therapy for SCLCs; however, its associated outcomes are heterogeneous. N6-methyladenosine (m6A) is a novel and decisive factor in tumour progression, chemotherapy resistance, and immunotherapy response. However, m6A modification in SCLC remains poorly understood. METHODS We systematically explored the molecular features and clinical significance of m6A regulators in SCLC. We then constructed an m6A regulator-based prognostic signature (m6A score) based on our examination of 256 cases with limited-stage SCLC (LS-SCLC) from three different cohorts-including an independent cohort that contained 150 cases with qPCR data. We additionally evaluated the relationships between the m6A score and adjuvant chemotherapy (ACT) benefits and the patients' responses to anti-PD-1 treatment. Immunohistochemical (IHC) staining and the HALO digital pathological platform were used to calculate CD8+ T cell density. RESULTS We observed abnormal somatic mutations and expressions of m6A regulators. Using the LASSO Cox model, a five-regulator-based (G3BP1, METTL5, ALKBH5, IGF2BP3, and RBM15B) m6A score was generated from the significant regulators to classify patients into high- and low-score groups. In the training cohort, patients with high scores had shorter overall survival (HR, 5.19; 2.75-9.77; P < 0.001). The prognostic accuracy of the m6A score was well validated in two independent cohorts (HR 4.6, P = 0.006 and HR 3.07, P < 0.001). Time-dependent ROC and C-index analyses found the m6A score to possess superior predictive power than other clinicopathological parameters. A multicentre multivariate analysis revealed the m6A score to be an independent prognostic indicator. Additionally, patients with low scores received a greater survival benefit from ACT, exhibited more CD8+ T cell infiltration, and were more responsive to cancer immunotherapy. CONCLUSIONS Our results, for the first time, affirm the significance of m6A regulators in LS-SCLC. Our multicentre analysis found that the m6A score was a reliable prognostic tool for guiding chemotherapy and immunotherapy selections for patients with SCLC.
Collapse
Affiliation(s)
- Zhihui Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Chaoqi Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yuejun Luo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Peng Wu
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qingpeng Zeng
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lide Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhaoyang Yang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Bo Zheng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Hua Zeng
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Fengwei Tan
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shugeng Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Nan Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| |
Collapse
|
|
39
|
Direct and Indirect Effect of TGFβ on Treg Transendothelial Recruitment in HCC Tissue Microenvironment. Int J Mol Sci 2021; 22:ijms222111765. [PMID: 34769191 PMCID: PMC8583957 DOI: 10.3390/ijms222111765] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 10/15/2021] [Accepted: 10/20/2021] [Indexed: 12/28/2022] Open
Abstract
The balance between anti-tumor and tumor-promoting immune cells, such as CD4+ Th1 and regulatory T cells (Tregs), respectively, is assumed to dictate the progression of hepatocellular carcinoma (HCC). The transforming growth factor beta (TGFβ) markedly shapes the HCC microenvironment, regulating the activation state of multiple leukocyte subsets and driving the differentiation of cancer associated fibroblasts (CAFs). The fibrotic (desmoplastic) reaction in HCC tissue strongly depends on CAFs activity. In this study, we attempted to assess the role of TGFβ on transendothelial migration of Th1-oriented and Treg-oriented CD4+ T cells via a direct or indirect, CAF-mediated mechanisms, respectively. We found that the blockage of TGFβ receptor I-dependent signaling in Tregs resulted in impaired transendothelial migration (TEM) of these cells. Interestingly, the secretome of TGFβ-treated CAFs inhibited the TEM of Tregs but not Th1 cells, in comparison to the secretome of untreated CAFs. In addition, we found a significant inverse correlation between alpha-SMA and FoxP3 (marker of Tregs) mRNA expression in a microarray analysis involving 78 HCCs, thus suggesting that TGFβ-activated stromal cells may counteract the trafficking of Tregs into the tumor. The apparent dual behavior of TGFβ as both pro- and anti-tumorigenic cytokines may add a further level of complexity to the mechanisms that regulate the interactions among cancerous, stromal, and immune cells within HCC, as well as other solid tumors, and contribute to better manipulation of the TGFβ signaling as a therapeutic target in HCC patients.
Collapse
|
|
40
|
Hyun J, Al Abo M, Dutta RK, Oh SH, Xiang K, Zhou X, Maeso-Díaz R, Caffrey R, Sanyal AJ, Freedman JA, Patierno SR, Moylan CA, Abdelmalek MF, Diehl AM. Dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes hepatobiliary carcinogenesis in non-alcoholic fatty liver disease. J Hepatol 2021; 75:623-633. [PMID: 33964370 PMCID: PMC8380690 DOI: 10.1016/j.jhep.2021.04.033] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 04/15/2021] [Accepted: 04/16/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD), the hepatic correlate of the metabolic syndrome, is a major risk factor for hepatobiliary cancer (HBC). Although chronic inflammation is thought to be the root cause of all these diseases, the mechanism whereby it promotes HBC in NAFLD remains poorly understood. Herein, we aim to evaluate the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis. METHODS We use murine NAFLD models, liver biopsies from patients with NAFLD, human liver cancer registry data, and studies in liver cancer cell lines. RESULTS Our results confirm the hypothesis that inflammation-related dysregulation of the ESRP2-NF2-YAP/TAZ axis promotes HB carcinogenesis, supporting a model whereby chronic inflammation suppresses hepatocyte expression of ESRP2, an RNA splicing factor that directly targets and activates NF2, a tumor suppressor that is necessary to constrain YAP/TAZ activation. The resultant loss of NF2 function permits sustained YAP/TAZ activity that drives hepatocyte proliferation and de-differentiation. CONCLUSION Herein, we report on a novel mechanism by which chronic inflammation leads to sustained activation of YAP/TAZ activity; this imposes a selection pressure that favors liver cells with mutations enabling survival during chronic oncogenic stress. LAY SUMMARY Non-alcoholic fatty liver disease (NAFLD) increases the risk of hepatobiliary carcinogenesis. However, the underlying mechanism remains unknown. Our study demonstrates that chronic inflammation suppresses hepatocyte expression of ESRP2, an adult RNA splicing factor that activates NF2. Thus, inactive (fetal) NF2 loses the ability to activate Hippo kinases, leading to the increased activity of downstream YAP/TAZ and promoting hepatobiliary carcinogenesis in chronically injured livers.
Collapse
Affiliation(s)
- Jeongeun Hyun
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA; Regeneration Next, Duke University School of Medicine, Durham, NC, USA; Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, South Korea; Department of Nanobiomedical Science and BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, South Korea; Department of Regenerative Dental Medicine, College of Dentistry, Dankook University, Cheonan, South Korea
| | - Muthana Al Abo
- Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Rajesh Kumar Dutta
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | - Seh Hoon Oh
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | - Kun Xiang
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, NC, USA
| | - Xiyou Zhou
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | - Raquel Maeso-Díaz
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | | | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Jennifer A Freedman
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Steven R Patierno
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA; Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA
| | - Cynthia A Moylan
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | - Manal F Abdelmalek
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA
| | - Anna Mae Diehl
- Department of Medicine, Duke University, Duke University Health System, Durham, NC, USA.
| |
Collapse
|
|
41
|
Liu K, Ou JHJ. Regulators of liver cancer stem cells. World J Stem Cells 2021; 13:1127-1133. [PMID: 34567430 PMCID: PMC8422929 DOI: 10.4252/wjsc.v13.i8.1127] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/06/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. It is often detected at a stage when there are few therapeutic options. Liver cancer stem cells (LCSCs) are highly tumorigenic and resistant to chemotherapy and radiation therapy. Their presence in HCC is a major reason why HCC is difficult to treat. The development of LCSCs is regulated by a variety of factors. This review summarizes recent advances on the factors that regulate the development of LCSCs. Due to the importance of LCSCs in the development of HCC, a better understanding of how LCSCs are regulated will help to improve the treatments for HCC patients.
Collapse
Affiliation(s)
- Kai Liu
- Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing 100069, China
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, United States
| |
Collapse
|
|
42
|
Gough NR, Xiang X, Mishra L. TGF-β Signaling in Liver, Pancreas, and Gastrointestinal Diseases and Cancer. Gastroenterology 2021; 161:434-452.e15. [PMID: 33940008 PMCID: PMC8841117 DOI: 10.1053/j.gastro.2021.04.064] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 04/05/2021] [Accepted: 04/25/2021] [Indexed: 02/06/2023]
Abstract
Genetic alterations affecting transforming growth factor-β (TGF-β) signaling are exceptionally common in diseases and cancers of the gastrointestinal system. As a regulator of tissue renewal, TGF-β signaling and the downstream SMAD-dependent transcriptional events play complex roles in the transition from a noncancerous disease state to cancer in the gastrointestinal tract, liver, and pancreas. Furthermore, this pathway also regulates the stromal cells and the immune system, which may contribute to evasion of the tumors from immune-mediated elimination. Here, we review the involvement of the TGF-β pathway mediated by the transcriptional regulators SMADs in disease progression to cancer in the digestive system. The review integrates human genomic studies with animal models that provide clues toward understanding and managing the complexity of the pathway in disease and cancer.
Collapse
Affiliation(s)
- Nancy R. Gough
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Xiyan Xiang
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York
| | - Lopa Mishra
- The Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research & Cold Spring Harbor Laboratory, Department of Medicine, Division of Gastroenterology and Hepatology, Northwell Health, Manhasset, New York; Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, District of Columbia.
| |
Collapse
|
|
43
|
Qi Y, Fang Q, Li Q, Ding H, Shu Q, Hu Y, Xin W, Fang L. MD2 blockage prevents the migration and invasion of hepatocellular carcinoma cells via inhibition of the EGFR signaling pathway. J Gastrointest Oncol 2021; 12:1873-1883. [PMID: 34532135 PMCID: PMC8421902 DOI: 10.21037/jgo-21-362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND The toll-like receptor (TLR) is an emerging signaling pathway in tumor invasion and metastasis. The activation of TLRs requires specific accessory proteins, such as the small secreted glycoprotein myeloid differentiation protein 2 (MD2), which contributes to ligand responsiveness. However, the role of MD2 in tumorigenesis and metastasis has rarely been reported. This study aimed to investigate the effects and underlying mechanisms of MD2 on the proliferation, migration, and invasion of hepatocellular carcinoma (HCC). METHODS Cell counting kit 8 (CCK8), cell colony formation, wound healing, and transwell assays were conducted to determine cell viability, proliferation, migration, and invasion, respectively. Quantitative real-time PCR (qRT-PCR) was performed to assess the expression of MD2 in HCC cell lines and human normal liver cell lines as well as the silencing efficiency of MD2 blockage. Western blot and qRT-PCR assays were performed to detect the protein and mRNA expression levels of epithelial mesenchymal transformation (EMT) markers and epidermal growth factor receptor (EGFR) signaling molecules. RESULTS MD2 was highly expressed in HCC tissues and cell lines. High expression of MD2 was associated with poor prognosis of HCC patients. In addition, MD2 silencing slightly inhibited the proliferation of HepG2 and HCCLM3, and significantly suppressed cell migration and invasion. Furthermore, MD2 blockage could distinctly prevent the EMT process by increasing the protein and mRNA levels of E-cadherin and Occludin, and decreasing the levels of Vimentin, N-cadherin, and Snail. Finally, the phosphorylation level of EGFR as well as its downstream molecular Src, Akt, I-κBα, and p65 were downregulated in HCC cells with MD2 silencing. CONCLUSIONS Our findings suggest that high expression of MD2 may affect the EMT, migration, and invasion via modulation of the EGFR pathway in HCC cells.
Collapse
Affiliation(s)
- Yajun Qi
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qilu Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Qinglin Li
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Haiying Ding
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
| | - Qi Shu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Yan Hu
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| | - Wenxiu Xin
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
- Department of Comprehensive Medical Oncology, Key Laboratory of Head and Neck Translational Research of Zhejiang Province, Zhejiang Cancer Hospital, Hangzhou, China
| | - Luo Fang
- Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China
- Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China
| |
Collapse
|
|
44
|
Rodriguez FD, Coveñas R. Biochemical Mechanisms Associating Alcohol Use Disorders with Cancers. Cancers (Basel) 2021; 13:cancers13143548. [PMID: 34298760 PMCID: PMC8306032 DOI: 10.3390/cancers13143548] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 07/01/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary Of all yearly deaths attributable to alcohol consumption globally, approximately 12% are due to cancers, representing approximately 0.4 million deceased individuals. Ethanol metabolism disturbs cell biochemistry by targeting the structure and function of essential biomolecules (proteins, nucleic acids, and lipids) and by provoking alterations in cell programming that lead to cancer development and cancer malignancy. A better understanding of the metabolic and cell signaling realm affected by ethanol is paramount to designing effective treatments and preventive actions tailored to specific neoplasias. Abstract The World Health Organization identifies alcohol as a cause of several neoplasias of the oropharynx cavity, esophagus, gastrointestinal tract, larynx, liver, or female breast. We review ethanol’s nonoxidative and oxidative metabolism and one-carbon metabolism that encompasses both redox and transfer reactions that influence crucial cell proliferation machinery. Ethanol favors the uncontrolled production and action of free radicals, which interfere with the maintenance of essential cellular functions. We focus on the generation of protein, DNA, and lipid adducts that interfere with the cellular processes related to growth and differentiation. Ethanol’s effects on stem cells, which are responsible for building and repairing tissues, are reviewed. Cancer stem cells (CSCs) of different origins suffer disturbances related to the expression of cell surface markers, enzymes, and transcription factors after ethanol exposure with the consequent dysregulation of mechanisms related to cancer metastasis or resistance to treatments. Our analysis aims to underline and discuss potential targets that show more sensitivity to ethanol’s action and identify specific metabolic routes and metabolic realms that may be corrected to recover metabolic homeostasis after pharmacological intervention. Specifically, research should pay attention to re-establishing metabolic fluxes by fine-tuning the functioning of specific pathways related to one-carbon metabolism and antioxidant processes.
Collapse
Affiliation(s)
- Francisco D. Rodriguez
- Department of Biochemistry and Molecular Biology, Faculty of Chemistry, University of Salamanca, 37007 Salamanca, Spain
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Correspondence: ; Tel.: +34-677-510-030
| | - Rafael Coveñas
- Group GIR USAL: BMD (Bases Moleculares del Desarrollo), 37007 Salamanca, Spain;
- Institute of Neurosciences of Castilla y León (INCYL), Laboratory of Neuroanatomy of the Peptidergic Systems, University of Salamanca, 37007 Salamanca, Spain
| |
Collapse
|
|
45
|
Yuan C, Pang L, Wang W, Ouyang Y, Guo X, Liu K. POU2F2-IL-31 Autoregulatory Circuit Converts Hepatocytes into the Origin Cells of Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2004683. [PMID: 37733361 PMCID: PMC10619474 DOI: 10.1002/advs.202004683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 02/07/2021] [Indexed: 09/22/2023]
Abstract
Hepatocellular carcinoma (HCC) originates from fully differentiated hepatocytes, but the decisive events for converting hepatocytes to the cells of origin for HCC are still unclear. Liver cancer stem cells (LCSCs) cause HCC but are not bona fide cells of origin. Here, the expressions of POU2F2 and IL-31 are identified in macroscopically normal livers of diethylnitrosamine-challenged mice. An autoregulatory circuit formed by mutual induction between POU2F2 and IL-31 drives hepatocytes to progress to LCSCs by acquiring stemness, as well as stimulates them to in vivo grow and malignantly progress. The development of the autoregulatory circuit is a decisive event for converting hepatocytes into the cells of origin, since hepatocytes expressing the circuit have acquired tumorigenic potential before progressing to LCSCs. Nonetheless, acquiring stemness is still required for the cells of origin to initiate hepatocarcinogenesis. The circuit also occurs in human cirrhotic tissues, partially elucidating how premalignant lesions progress to HCC.
Collapse
Affiliation(s)
- Chunwang Yuan
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
| | - Lijun Pang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Wenjing Wang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Yabo Ouyang
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Xianghua Guo
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| | - Kai Liu
- Capital Medical University Affiliated to Beijing You An HospitalBeijing100069China
- Beijing Institute of HepatologyBeijing100069China
| |
Collapse
|
|
46
|
The TGF-β Pathway: A Pharmacological Target in Hepatocellular Carcinoma? Cancers (Basel) 2021; 13:cancers13133248. [PMID: 34209646 PMCID: PMC8268320 DOI: 10.3390/cancers13133248] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/23/2021] [Accepted: 06/24/2021] [Indexed: 02/07/2023] Open
Abstract
Transforming Growth Factor-beta (TGF-β) superfamily members are essential for tissue homeostasis and consequently, dysregulation of their signaling pathways contributes to the development of human diseases. In the liver, TGF-β signaling participates in all the stages of disease progression from initial liver injury to hepatocellular carcinoma (HCC). During liver carcinogenesis, TGF-β plays a dual role on the malignant cell, behaving as a suppressor factor at early stages, but contributing to later tumor progression once cells escape from its cytostatic effects. Moreover, TGF-β can modulate the response of the cells forming the tumor microenvironment that may also contribute to HCC progression, and drive immune evasion of cancer cells. Thus, targeting the TGF-β pathway may constitute an effective therapeutic option for HCC treatment. However, it is crucial to identify biomarkers that allow to predict the response of the tumors and appropriately select the patients that could benefit from TGF-β inhibitory therapies. Here we review the functions of TGF-β on HCC malignant and tumor microenvironment cells, and the current strategies targeting TGF-β signaling for cancer therapy. We also summarize the clinical impact of TGF-β inhibitors in HCC patients and provide a perspective on its future use alone or in combinatorial strategies for HCC treatment.
Collapse
|
|
47
|
Conde de la Rosa L, Garcia-Ruiz C, Vallejo C, Baulies A, Nuñez S, Monte MJ, Marin JJG, Baila-Rueda L, Cenarro A, Civeira F, Fuster J, Garcia-Valdecasas JC, Ferrer J, Karin M, Ribas V, Fernandez-Checa JC. STARD1 promotes NASH-driven HCC by sustaining the generation of bile acids through the alternative mitochondrial pathway. J Hepatol 2021; 74:1429-1441. [PMID: 33515644 PMCID: PMC8573791 DOI: 10.1016/j.jhep.2021.01.028] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 01/10/2021] [Accepted: 01/13/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Besides their physiological role in bile formation and fat digestion, bile acids (BAs) synthesised from cholesterol in hepatocytes act as signalling molecules that modulate hepatocellular carcinoma (HCC). Trafficking of cholesterol to mitochondria through steroidogenic acute regulatory protein 1 (STARD1) is the rate-limiting step in the alternative pathway of BA generation, the physiological relevance of which is not well understood. Moreover, the specific contribution of the STARD1-dependent BA synthesis pathway to HCC has not been previously explored. METHODS STARD1 expression was analyzed in a cohort of human non-alcoholic steatohepatitis (NASH)-derived HCC specimens. Experimental NASH-driven HCC models included MUP-uPA mice fed a high-fat high-cholesterol (HFHC) diet and diethylnitrosamine (DEN) treatment in wild-type (WT) mice fed a HFHC diet. Molecular species of BAs and oxysterols were analyzed by mass spectrometry. Effects of NASH-derived BA profiles were investigated in tumour-initiated stem-like cells (TICs) and primary mouse hepatocytes (PMHs). RESULTS Patients with NASH-associated HCC exhibited increased hepatic expression of STARD1 and an enhanced BA pool. Using NASH-driven HCC models, STARD1 overexpression in WT mice increased liver tumour multiplicity, whereas hepatocyte-specific STARD1 deletion (Stard1ΔHep) in WT or MUP-uPA mice reduced tumour burden. These findings mirrored the levels of unconjugated primary BAs, β-muricholic acid and cholic acid, and their tauroconjugates in STARD1-overexpressing and Stard1ΔHep mice. Incubation of TICs or PMHs with a mix of BAs mimicking this profile stimulated expression of genes involved in pluripotency, stemness and inflammation. CONCLUSIONS The study reveals a previously unrecognised role of STARD1 in HCC pathogenesis, wherein it promotes the synthesis of primary BAs through the mitochondrial pathway, the products of which act in TICs to stimulate self-renewal, stemness and inflammation. LAY SUMMARY Effective therapy for hepatocellular carcinoma (HCC) is limited because of our incomplete understanding of its pathogenesis. The contribution of the alternative pathway of bile acid (BA) synthesis to HCC development is unknown. We uncover a key role for steroidogenic acute regulatory protein 1 (STARD1) in non-alcoholic steatohepatitis-driven HCC, wherein it stimulates the generation of BAs in the mitochondrial acidic pathway, the products of which stimulate hepatocyte pluripotency and self-renewal, as well as inflammation.
Collapse
Affiliation(s)
- Laura Conde de la Rosa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Carmen Garcia-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Carmen Vallejo
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Anna Baulies
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Susana Nuñez
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maria J Monte
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Jose J G Marin
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Experimental Hepatology and Drug Targeting (HEVEFARM), Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain
| | - Lucia Baila-Rueda
- Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain; CIBERCV, Madrid, Spain
| | - Ana Cenarro
- Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain; CIBERCV, Madrid, Spain
| | - Fernando Civeira
- Instituto Investigación Sanitaria Aragón, Hospital Universitario Miguel Servet, Zaragoza, Spain; CIBERCV, Madrid, Spain
| | - Josep Fuster
- HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Juan C Garcia-Valdecasas
- HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Joana Ferrer
- HepatoBilioPancreatic Surgery and Liver and Pancreatic Transplantation Unit, Department of Surgery, ICMDiM, Hospital Clinic, University of Barcelona, Barcelona, Spain
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Vicent Ribas
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain.
| | - Jose C Fernandez-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain; Liver Unit, Hospital Clinic I Provincial de Barcelona, Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, Madrid, Spain; Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|
|
48
|
Tang M, Yang M, Wu G, Mo S, Wu X, Zhang S, Yu R, Hu Y, Xu Y, Li Z, Liao X, Li J, Song L. Epigenetic Induction of Mitochondrial Fission Is Required for Maintenance of Liver Cancer-Initiating Cells. Cancer Res 2021; 81:3835-3848. [PMID: 34049973 DOI: 10.1158/0008-5472.can-21-0436] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/20/2021] [Accepted: 05/27/2021] [Indexed: 11/16/2022]
Abstract
Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.
Collapse
Affiliation(s)
- Miaoling Tang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Meisongzhu Yang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Geyan Wu
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Shuang Mo
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xingui Wu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Shuxia Zhang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ruyuan Yu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yameng Hu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Yingru Xu
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ziwen Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Xinyi Liao
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jun Li
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
| | - Libing Song
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
| |
Collapse
|
|
49
|
Chen H, Nio K, Yamashita T, Okada H, Li R, Suda T, Li Y, Doan PTB, Seki A, Nakagawa H, Toyama T, Terashima T, Iida N, Shimakami T, Takatori H, Kawaguchi K, Sakai Y, Yamashita T, Mizukoshi E, Honda M, Kaneko S. BMP9-ID1 signaling promotes EpCAM-positive cancer stem cell properties in hepatocellular carcinoma. Mol Oncol 2021; 15:2203-2218. [PMID: 33834612 PMCID: PMC8333780 DOI: 10.1002/1878-0261.12963] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/26/2021] [Accepted: 04/07/2021] [Indexed: 12/15/2022] Open
Abstract
The malignant nature of hepatocellular carcinoma (HCC) is closely related to the presence of cancer stem cells (CSCs). Bone morphologic protein 9 (BMP9), a member of the transforming growth factor‐beta (TGF‐β) superfamily, was recently reported to be involved in liver diseases including cancer. We aimed to elucidate the role of BMP9 signaling in HCC‐CSC properties and to assess the therapeutic effect of BMP receptor inhibitors in HCC. We have identified that high BMP9 expression in tumor tissues or serum from patients with HCC leads to poorer outcome. BMP9 promoted CSC properties in epithelial cell adhesion molecule (EpCAM)‐positive HCC subtype via enhancing inhibitor of DNA‐binding protein 1 (ID1) expression in vitro. Additionally, ID1 knockdown significantly repressed BMP9‐promoted HCC‐CSC properties by suppressing Wnt/β‐catenin signaling. Interestingly, cells treated with BMP receptor inhibitors K02288 and LDN‐212854 blocked HCC‐CSC activation by inhibiting BMP9‐ID1 signaling, in contrast to cells treated with the TGF‐β receptor inhibitor galunisertib. Treatment with LDN‐212854 suppressed HCC tumor growth by repressing ID1 and EpCAM in vivo. Our study demonstrates the pivotal role of BMP9‐ID1 signaling in promoting HCC‐CSC properties and the therapeutic potential of BMP receptor inhibitors in treating EpCAM‐positive HCC. Therefore, targeting BMP9‐ID1 signaling could offer novel therapeutic options for patients with malignant HCC.
Collapse
Affiliation(s)
- Han Chen
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Kouki Nio
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Taro Yamashita
- Department of General MedicineKanazawa University HospitalJapan
| | - Hikari Okada
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Ru Li
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Tsuyoshi Suda
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Yingyi Li
- Department of GastroenterologyKanazawa University HospitalJapan
| | | | - Akihiro Seki
- Department of GastroenterologyKanazawa University HospitalJapan
| | | | - Tadashi Toyama
- Innovative Clinical Research CenterKanazawa UniversityJapan
| | | | - Noriho Iida
- Department of GastroenterologyKanazawa University HospitalJapan
| | | | - Hajime Takatori
- Department of GastroenterologyKanazawa University HospitalJapan
| | | | - Yoshio Sakai
- Department of GastroenterologyKanazawa University HospitalJapan
| | | | | | - Masao Honda
- Department of GastroenterologyKanazawa University HospitalJapan
| | - Shuichi Kaneko
- Department of GastroenterologyKanazawa University HospitalJapan
| |
Collapse
|
|
50
|
Zarębska I, Gzil A, Durślewicz J, Jaworski D, Antosik P, Ahmadi N, Smolińska-Świtała M, Grzanka D, Szylberg Ł. The clinical, prognostic and therapeutic significance of liver cancer stem cells and their markers. Clin Res Hepatol Gastroenterol 2021; 45:101664. [PMID: 33667731 DOI: 10.1016/j.clinre.2021.101664] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/24/2020] [Accepted: 02/17/2021] [Indexed: 02/04/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most common cause of death among cancers. The poor prognosis of HCC might be caused by a population of cancer stem cells (CSC). CSC have similar characteristics to normal stem cells and are responsible for cancer recurrence, chemoresistance, radioresistance and metastasis. Liver cancer stem cells (LCSC) are identified via specific surface markers, such as CD44, CD90, CD133, and EpCAM (CD326). Recent studies suggested a complex interaction between mentioned LCSC markers and clinical features of HCC. A high expression of CSC is correlated with a negative prognostic factor after surgical resection of HCC and is connected with more aggressive tumor behavior. Moreover, LCSC might be responsible for increasing resistance to sorafenib, a kinase inhibitor drug. A reduction in the LCSC population may be crucial to successful advanced HCC therapy.
Collapse
Affiliation(s)
- Izabela Zarębska
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland.
| | - Arkadiusz Gzil
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Damian Jaworski
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Paulina Antosik
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Navid Ahmadi
- Chair and Department of Oncologic Pathology and Prophylactics, Greater Poland Cancer Center, Poznan University of Medical Sciences, Poland
| | - Marta Smolińska-Świtała
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland
| | - Łukasz Szylberg
- Department of Clinical Pathomorphology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Sklodowskiej-Curie Str. 9, 85-094 Bydgoszcz, Poland; Department of Pathomorphology, Military Clinical Hospital, Bydgoszcz, Poland; Department of Tumor Pathology and Pathomorphology, Oncology Center, Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland
| |
Collapse
|