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Wang D, Zhu L, Liu H, Feng X, Zhang C, Li T, Liu B, Liu L, Sun J, Chang H, Chen S, Guo S, Yang W. Huangqin tang alleviates colitis-associated colorectal cancer via amino acids homeostasisand PI3K/AKT/mtor pathway modulation. JOURNAL OF ETHNOPHARMACOLOGY 2024; 334:118597. [PMID: 39034016 DOI: 10.1016/j.jep.2024.118597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/29/2024] [Accepted: 07/17/2024] [Indexed: 07/23/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Huangqin Tang (HQT), a traditional Chinese medicine formula, is commonly used in clinical practice for the treatment of inflammatory bowel diseases. It has been reported that HQT exerts antitumor effects on colitis-associated colorectal cancer (CAC). However, the mechanism by which HQT interferes with the inflammation-to-cancer transformation remains unclear. AIMS OF THE STUDY The purpose of this study was to dynamically evaluate the efficacy of HQT in alleviating or delaying CAC and to reveal the underlying mechanism. METHODS We established a mouse model of CAC using azoxymethane combined with 1.5% dextran sodium sulphate. The efficacy of HQT was evaluated based on pathological sections and serum biochemical indices. Subsequently, amino acids (AAs) metabolism analyses were performed using ultra-performance liquid chromatography-tandem mass spectrometry, and the phosphatidylinositol 3 kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR) pathway was detected by western blotting. RESULTS The data demonstrated that HQT could alleviate the development of CAC in the animal model. HQT effectively reduced the inflammatory response, particularly interleukin-6 (IL-6), in the inflammation induction stage, as well as in the stages of proliferation initiation and tumorigenesis. During the proliferation initiation and tumorigenesis stages, immunohistochemistry staining showed that the expression of the proliferation marker Ki67 was reduced, while apoptosis was increased in the HQT group. Accordingly, HQT substantially decreased the levels of specific AAs in the colon with CAC, including glutamic acid, glutamine, arginine, and isoleucine. Furthermore, HQT significantly inhibited the activated PI3K/AKT/mTOR pathway, which may contribute to suppression of cell proliferation and enhancement of apoptosis. CONCLUSION HQT is effective in alleviating and delaying the colon "inflammation-to-cancer". The mechanism of action may involve HQT maintained AAs metabolism homeostasis and regulated PI3K/AKT/mTOR pathway, so as to maintain the balance between proliferation and apoptosis, and then interfere in the occurrence and development of CAC.
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Affiliation(s)
- Dunfang Wang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Lin Zhu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Haifan Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Xue Feng
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Caijuan Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Tao Li
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Bin Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Li Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Jingwei Sun
- Beijing University of Chinese Medicine, Beijing, 100700, China.
| | - Hao Chang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Siyuan Chen
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Shanshan Guo
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
| | - Weipeng Yang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China.
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Carbajal-López B, Martínez-Gutierrez AD, Madrigal-Santillán EO, Calderillo-Ruiz G, Morales-González JA, Coronel-Hernández J, Lockhart J, Millan-Catalan O, Mendoza-Rodriguez MG, Lino-Silva LS, Calderillo-Trejo G, Sumagin R, Pérez-Plasencia C, Pérez-Yépez EA. miR-3065-5p and miR-26a-5p as Clinical Biomarkers in Colorectal Cancer: A Translational Study. Cancers (Basel) 2024; 16:3649. [PMID: 39518087 PMCID: PMC11545460 DOI: 10.3390/cancers16213649] [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: 09/27/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: The prognosis of colorectal cancer (CRC) is mainly based on the clinical stage; however, CRC is considered a complex disease due to its molecular heterogeneity. The development of novel biomarkers to improve patients' diagnosis and prognosis remains fundamental. Methods: A cohort of forty-nine CRC patients from the National Cancer Institute of Mexico was included to collect clinical and miRNA expression data. The expression of a group of miRNAs was compared between CRC and non-tumoral adjacent tissues. Prognosis assessment considering each miRNA expression was tested using Kaplan-Meier survival curves and Cox regressions. Statistical significance was defined as p ≤ 0.05. Trial registration: Retrospective study No.2021/046. Results: miR-3065-5p and miR-26a-5p expression differed between non-tumoral adjacent and tumoral tissues (p = 0.02). In terms of overall survival (OS), patients with low expression of miR-3065-5p had a median OS of 70 months, while patients with high levels did not reach the median OS (p = 0.041). Male patients with low expression of this miRNA had an OS of 70 months, whereas patients with high levels did not reach the median OS (p = 0.050). Under uni-multivariate analysis, clinical stage (HR: 1.30, CI 1.23-2.30; p: 0.001) and low levels of miR-3065-5p (HR: 1.30, CI 1.23-2.30; p: 0.001) were determined as predictor factors of OS. To this end, we designed the "Prognosis miRNAs assessment in cancer" (PROMIR-C) algorithm, which integrated clinical features with miR-3065-5p expression levels. Conclusions: These findings support the clinical utility of miR-26a-5p and miR-3065-5p in the diagnosis and prognosis of CRC. PROMIR-C is a fundamental tool for clinicians in treatment decision-making, prognosis assessment, and outcome of CRC.
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Affiliation(s)
- Berenice Carbajal-López
- Programa de Doctorado en Investigación en Medicina, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico;
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (A.D.M.-G.); (J.C.-H.); (O.M.-C.)
| | | | - Eduardo O. Madrigal-Santillán
- Laboratorio de Medicina de la Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico; (E.O.M.-S.); (J.A.M.-G.)
| | - Germán Calderillo-Ruiz
- Unidad Funcional de Gastroenterología, Oncología Médica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (G.C.-R.); (G.C.-T.)
| | - José Antonio Morales-González
- Laboratorio de Medicina de la Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México 11340, Mexico; (E.O.M.-S.); (J.A.M.-G.)
| | - Jossimar Coronel-Hernández
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (A.D.M.-G.); (J.C.-H.); (O.M.-C.)
| | - Joey Lockhart
- Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St., Chicago, IL 60611, USA; (J.L.); (R.S.)
| | - Oliver Millan-Catalan
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (A.D.M.-G.); (J.C.-H.); (O.M.-C.)
| | - Monica G. Mendoza-Rodriguez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla 04510, Mexico;
| | - Leonardo S. Lino-Silva
- Departamento de Anatomía Patológica, Instituto Nacional de Cancerología (INCan), Ciudad de Mexico 14080, Mexico;
| | - Germán Calderillo-Trejo
- Unidad Funcional de Gastroenterología, Oncología Médica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (G.C.-R.); (G.C.-T.)
| | - Ronen Sumagin
- Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St., Chicago, IL 60611, USA; (J.L.); (R.S.)
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (A.D.M.-G.); (J.C.-H.); (O.M.-C.)
- Laboratorio de Genómica, FES-Iztacala, Universidad Nacional Autónoma de México (UNAM), Iztacala, Tlalnepantla 54090, Mexico
| | - Eloy Andrés Pérez-Yépez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan 14080, Mexico; (A.D.M.-G.); (J.C.-H.); (O.M.-C.)
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Barbagallo D, Ponti D, Bassani B, Bruno A, Pulze L, Akkihal SA, George-William JN, Gundamaraju R, Campomenosi P. MiR-223-3p in Cancer Development and Cancer Drug Resistance: Same Coin, Different Faces. Int J Mol Sci 2024; 25:8191. [PMID: 39125761 PMCID: PMC11311375 DOI: 10.3390/ijms25158191] [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: 06/06/2024] [Revised: 07/18/2024] [Accepted: 07/23/2024] [Indexed: 08/12/2024] Open
Abstract
MicroRNAs (miRNAs) are mighty post-transcriptional regulators in cell physiology and pathophysiology. In this review, we focus on the role of miR-223-3p (henceforth miR-223) in various cancer types. MiR-223 has established roles in hematopoiesis, inflammation, and most cancers, where it can act as either an oncogenic or oncosuppressive miRNA, depending on specific molecular landscapes. MiR-223 has also been linked to either the sensitivity or resistance of cancer cells to treatments in a context-dependent way. Through this detailed review, we highlight that for some cancers (i.e., breast, non-small cell lung carcinoma, and glioblastoma), the oncosuppressive role of miR-223 is consistently reported in the literature, while for others (i.e., colorectal, ovarian, and pancreatic cancers, and acute lymphocytic leukemia), an oncogenic role prevails. In prostate cancer and other hematological malignancies, although an oncosuppressive role is frequently described, there is less of a consensus. Intriguingly, NLRP3 and FBXW7 are consistently identified as miR-223 targets when the miRNA acts as an oncosuppressor or an oncogene, respectively, in different cancers. Our review also describes that miR-223 was increased in biological fluids or their extracellular vesicles in most of the cancers analyzed, as compared to healthy or lower-risk conditions, confirming the potential application of this miRNA as a diagnostic and prognostic biomarker in the clinic.
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Affiliation(s)
- Davide Barbagallo
- Department of Biomedical and Biotechnological Sciences, Section of Biology and Genetics “Giovanni Sichel”, University of Catania, Via Santa Sofia 89, 95123 Catania, Italy
- Interdisciplinary Research Centre on the Diagnosis and Therapy of Brain Tumors, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy
| | - Donatella Ponti
- Department of Medical-Surgical Sciences and Biotechnologies, University of Rome Sapienza, Corso della Repubblica 79, 04100 Latina, Italy;
| | - Barbara Bassani
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Via Fantoli 16/15, 20138 Milano, Italy; (B.B.); (A.B.)
| | - Antonino Bruno
- Laboratory of Innate Immunity, Unit of Molecular Pathology, Biochemistry, and Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Via Fantoli 16/15, 20138 Milano, Italy; (B.B.); (A.B.)
- Department of Biotechnology and Life Sciences, DBSV, University of Insubria, Via J.H. Dunant 3, 21100 Varese, Italy;
| | - Laura Pulze
- Department of Biotechnology and Life Sciences, DBSV, University of Insubria, Via J.H. Dunant 3, 21100 Varese, Italy;
| | - Shreya A. Akkihal
- Independent Researcher, 35004 SE Swenson St, Snoqualmie, WA 98065, USA;
| | - Jonahunnatha N. George-William
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Fratelli Cervi, 93, 20054 Segrate, Italy;
| | - Rohit Gundamaraju
- Department of Laboratory Medicine, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA;
- ER Stress and Mucosal Immunology Team, School of Health Sciences, University of Tasmania, Launceston, TAS 7248, Australia
| | - Paola Campomenosi
- Department of Biotechnology and Life Sciences, DBSV, University of Insubria, Via J.H. Dunant 3, 21100 Varese, Italy;
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Li D, Fan G, Zhou Y. Chitinase 3 like-1 activates the Akt pathway, inducing NF-κB-dependent release of pro-inflammatory cytokines and promoting the proliferative ability in nasopharyngeal carcinoma cells. Cytokine 2024; 179:156631. [PMID: 38710115 DOI: 10.1016/j.cyto.2024.156631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 04/22/2024] [Accepted: 04/28/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Chitinase 3 like-1 (CHI3L1) has been reported to function as an oncogene in many types of cancer. However, the biological function of CHI3L1 in nasopharyngeal carcinoma (NPC) remains unknown. METHODS Differentially expressed genes (DEGs) in NPC tissues in GSE64634 and GSE12452 were downloaded from Gene Expression Omnibus (GEO). CHI3L1, interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) mRNA expression was examined by qRT-PCR. Cell proliferation was evaluated by CCK-8 and EdU incorporation assays. Western blot analysis was used to measure the changes of CHI3L1, nuclear factor-κappaB (NF-κB), and protein kinase B (Akt) pathways. Gene ontology (GO) enrichment and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses were performed using DAVID database. RESULTS We identified 3 overlapping DEGs using Draw Venn diagram, among which CHI3L1 was chosen for the following analyses. CHI3L1 was upregulated in NPC tissues and cells. CHI3L1 silencing suppressed inflammatory response by inactivating the NF-κB pathway and inhibited cell proliferation in NPC cells. On the contrary, CHI3L1 overexpression induced inflammatory response by activating the NF-κB pathway and promoted cell proliferation in NPC cells. According to GO and KEGG analyses, CHI3L1 positive regulates Akt signaling and is enriched in the PI3K-Akt pathway. CHI3L1 knockdown inhibited the Akt pathway, and CHI3L1 overexpression activated the Akt pathway in NPC cells. Akt overexpression abolished the effects of CHI3L1 knockdown on inflammatory response, NF-κB pathway, and proliferation in NPC cells. On the contrary, Akt knockdown abolished the effects of CHI3L1 overexpression on inflammatory response, NF-κB pathway, and proliferation in NPC cells. CONCLUSION CHI3L1 knockdown inhibited NF-κB-dependent inflammatory response and promoting proliferation in NPC cells by inactivating the Akt pathway.
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Affiliation(s)
- Dajun Li
- Department of ENT, Nanyang First People's Hospital, Nanyang, China.
| | - Gai Fan
- Department of ENT, Nanyang First People's Hospital, Nanyang, China
| | - Yeqi Zhou
- Department of Radiotherapy, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an Second People's Hospital, Huai'an, China
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Wang C, Yang Y, Jiang C, Xi C, Yin Y, Wu H, Qian C. Exosomes Derived from hucMSCs Primed with IFN-γ Suppress the NF-κB Signal Pathway in LPS-Induced ALI by Modulating the miR-199b-5p/AFTPH Axis. Cell Biochem Biophys 2024; 82:647-658. [PMID: 38216808 DOI: 10.1007/s12013-023-01208-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 11/30/2023] [Indexed: 01/14/2024]
Abstract
Exosomes (exos) are primarily responsible for the process of mesenchymal stem cells (MSCs) treatment for acute lung injury (ALI), but the mechanism remains unclear, particularly in altered microenvironment. Therefore, this study aimed to investigate the potential mechanism of exos derived from human umbilical cord mesenchymal stem cells (hucMSCs) primed with interferon-gamma (IFN-γ) on ALI and to propose a promising and cell-free strategy. This study extracted exos from hucMSCs supernatant primed and unprimed with IFN-γ marked with IFN-γ-exos and CON-exos, which were identified and traced. IFN-γ-exos administration to ALI models suppressed the NF-κB signaling pathway compared to CON-exos, which were quantified through western blot and immunohistochemical staining. Reverse transcription-quantitative polymerase chain reaction validated miR-199b-5p expression in the IFN-γ-exos and CON-exos treatment groups. Data analysis, a dual-luciferase reporter assay, and cell transfection were conducted to investigate the target binding between miR-199b-5p and Aftiphilin (AFTPH), with AFTPH expression analyzed via cell immunofluorescence and western blot. Co-immunoprecipitation was conducted for the interaction between AFTPH and NF-κB p65. The result revealed that miR-199b-5p was down-regulated in the IFN-γ-exos treatment group, which had a target binding site with AFTPH, and an interaction with NF-κB p65. Consequently, IFN-γ-exos inhibited the NF-κB signaling pathway in ALI in vitro and in vivo through the miR-199b-5p/AFTPH axis. Our results demonstrated new directions of novel and targeted treatment for ALI.
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Affiliation(s)
- Chun Wang
- Kunming Medical University, Kunming, Yunnan, China
- Department of Emergency Intensive Care Unit, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yiran Yang
- Kunming Medical University, Kunming, Yunnan, China
| | - Chen Jiang
- Kunming Medical University, Kunming, Yunnan, China
| | - Cheng Xi
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Yunxiang Yin
- Department of Emergency Intensive Care Unit, Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
| | - Haiying Wu
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
| | - Chuanyun Qian
- Department of Emergency, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China.
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Zhang Y, Wang Y, Xin E, Zhang Z, Ma D, Liu T, Gao F, Bian T, Sun Y, Wang M, Wang Z, Yan X, Li Y. Network pharmacology and experimental verification reveal the mechanism of Hedysari Radix and Curcumae Rhizoma with the optimal compatibility ratio against colitis-associated colorectal cancer. JOURNAL OF ETHNOPHARMACOLOGY 2024; 322:117555. [PMID: 38110130 DOI: 10.1016/j.jep.2023.117555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/20/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The herb pair Astragali Radix (AR) and Curcumae Rhizoma (vinegar-processed, VPCR), derived from the traditional Chinese medicine (TCM) text 'Yixuezhongzhongcanxilu', have long been used to treat gastrointestinal diseases, notably colitis-associated colorectal cancer (CAC). Hedysari Radix (HR), belonging to the same Leguminosae family as AR but from a different genus, is traditionally used as a substitute for AR when paired with VPCR in the treatment of CAC. However, the optimal compatibility ratio for HR-VPCR against CAC and the underlying mechanisms remain unclear. AIM OF THE STUDY To investigate the optimal compatibility ratio and underlying mechanisms of HR-VPCR against CAC using a combination of comparative pharmacodynamics, network pharmacology, and experimental verification. MATERIALS AND METHODS The efficacy of different compatibility ratios of HR-VPCR against CAC was evaluated using various indicators, including the body weight, colon length, tumor count, survival rate, disease activity index (DAI) score, Haemotoxylin and Eosin (H&E) pathological sections, inflammation cytokines (IL-1β, IL-6, IL-10, TNF-α), tumor markers (K-Ras, p53), and intestinal permeability proteins (claudin-1, E-cadherin, mucin-2). Then, the optimal compatibility ratio of HR-VPCR against CAC was determined based on the fuzzy matter-element analysis by integrating the above indicators. After high-performance liquid chromatography (HPLC) analysis for the optimal compatibility ratio of HR-VPCR, potential active components of HR-VPCR were identified by TCMSP and the previous bibliographies. Swiss Targets and GeneCards were adopted to predict the targets of the active components and the targets of CAC, respectively. Then, the common targets of HR-VPCR against CAC were obtained by Venn analysis. PPI networks were constructed in STRING. GO and KEGG enrichments were visualized by the David database. Finally, the predicted pathway was experimentally validated via Western blot. RESULTS Various compatibility ratios of HR-VPCR demonstrated notable therapeutic effects to some extent, evidenced by improvements in body weight, colon length, tumor count, pathological symptoms (DAI score), colon and organ indexes, survival rate, and modulation of inflammation factors (IL-1β, IL-6, IL-10, TNF-α), as well as tumor markers (K-Ras, p53), and down-regulation of intestinal permeability proteins (claudin-1, E-cadherin, mucin-2) in CAC mice. Among these ratios, the ratio 4:1 represents the optimal compatibility ratio by the fuzzy matter-element analysis. Thirty active components of HR-VPCR were carefully selected, targeting 553 specific genes. Simultaneously, 2022 targets associated with CAC were identified. 88 common targets were identified after generating a Venn plot. Following PPI network analysis, 29 core targets were established, with AKT1 ranking highest among them. Further analysis via GO and KEGG enrichment identified the PI3K-AKT signaling pathway as a potential mechanism. Experimental validation confirmed that HR-VPCR intervention effectively reversed the activated PI3K-AKT signaling pathway. CONCLUSIONS The optimal compatibility ratio for the HR-VPCR herb pair in alleviating CAC is 4:1. HR-VPCR exerts its effects by alleviating intestinal inflammation, improving intestinal permeability, and regulating the PI3K-AKT signaling pathway.
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Affiliation(s)
- Yugui Zhang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Yanjun Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Erdan Xin
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Zhuanhong Zhang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Dingcai Ma
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Ting Liu
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Feiyun Gao
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Tiantian Bian
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Yujing Sun
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Scientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Maomao Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Zhe Wang
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Xingke Yan
- College of Acupuncture-Moxibustion and Tuina, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
| | - Yuefeng Li
- College of Pharmacy, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Key Laboratory of Standard and Quality of Chinese Medicine Research of Gansu, Engineering Research Center of Chinese Medicine Pharmaceutical Process of Gansu, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China; Scientific Research and Experimental Center, Gansu University of Chinese Medicine, Lanzhou, 730000, PR China.
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Emerging Role of Plant-Based Dietary Components in Post-Translational Modifications Associated with Colorectal Cancer. Life (Basel) 2023; 13:life13020264. [PMID: 36836621 PMCID: PMC9962725 DOI: 10.3390/life13020264] [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: 12/30/2022] [Revised: 01/12/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. Its main modifiable risk factors are diet, alcohol consumption, and smoking. Thus, the right approach through lifestyle changes may lead to its prevention. In fact, some natural dietary components have exhibited chemopreventive activity through modulation of cellular processes involved in CRC development. Although cancer is a multi-factorial process, the study of post-translational modifications (PTMs) of proteins associated with CRC has recently gained interest, as inappropriate modification is closely related to the activation of cell signalling pathways involved in carcinogenesis. Therefore, this review aimed to collect the main PTMs associated with CRC, analyse the relationship between different proteins that are susceptible to inappropriate PTMs, and review the available scientific literature on the role of plant-based dietary compounds in modulating CRC-associated PTMs. In summary, this review suggested that some plant-based dietary components such as phenols, flavonoids, lignans, terpenoids, and alkaloids may be able to correct the inappropriate PTMs associated with CRC and promote apoptosis in tumour cells.
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Theabrownin Alleviates Colorectal Tumorigenesis in Murine AOM/DSS Model via PI3K/Akt/mTOR Pathway Suppression and Gut Microbiota Modulation. Antioxidants (Basel) 2022; 11:antiox11091716. [PMID: 36139789 PMCID: PMC9495753 DOI: 10.3390/antiox11091716] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/27/2022] [Accepted: 08/27/2022] [Indexed: 11/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common and fatal cancers worldwide, yet therapeutic options for CRC often exhibit strong side effects which cause patients’ well-being to deteriorate. Theabrownin (TB), an antioxidant from Pu-erh tea, has previously been reported to have antitumor effects on non-small-cell lung cancer, osteosarcoma, hepatocellular carcinoma, gliomas, and melanoma. However, the potential antitumor effect of TB on CRC has not previously been investigated in vivo. The present study therefore aimed to investigate the antitumor effect of TB on CRC and the underlying mechanisms. Azoxymethane (AOM)/dextran sodium sulphate (DSS) was used to establish CRC tumorigenesis in a wild type mice model. TB was found to significantly reduce the total tumor count and improve crypt length and fibrosis of the colon when compared to the AOM/DSS group. Immunohistochemistry staining shows that the expression of the proliferation marker, Ki67 was reduced, while cleaved caspase 3 was increased in the TB group. Furthermore, TB significantly reduced phosphorylation of phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt), and the downstream mechanistic target of rapamycin (mTOR)and cyclin D1 protein expression, which might contribute to cell proliferation suppression and apoptosis enhancement. The 16s rRNA sequencing revealed that TB significantly modulated the gut microbiota composition in AOM/DSS mice. TB increased the abundance of short chain fatty acid as well as SCFA-producing Prevotellaceae and Alloprevotella, and it decreased CRC-related Bacteroidceae and Bacteroides. Taken together, our results suggest that TB could inhibit tumor formation and potentially be a promising candidate for CRC treatment.
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10
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Martínez-Gutierrez A, Carbajal-Lopez B, Bui TM, Mendoza-Rodriguez M, Campos-Parra AD, Calderillo-Ruiz G, Cantú-De Leon D, Madrigal-Santillán EO, Sumagin R, Pérez-Plasencia C, Pérez-Yépez EA. A microRNA panel that regulates proinflammatory cytokines as diagnostic and prognosis biomarkers in colon cancer. Biochem Biophys Rep 2022; 30:101252. [PMID: 35313644 PMCID: PMC8933814 DOI: 10.1016/j.bbrep.2022.101252] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/23/2022] [Accepted: 03/13/2022] [Indexed: 12/24/2022] Open
Abstract
Colon cancer (CC) is the third most common neoplasm and the fourth cause of cancer-related death worldwide in both sexes. It has been established that inflammation plays a critical role in tumorigenesis and progression of CC. Immune, stromal and tumor cells supply the tumor microenvironment with pro-inflammatory cytokines such as interleukin 1β, TNFα, IL-6 and IL-11, to hyperactivate signaling pathways linked to cancerous processes. Recent findings suggest a putative role of microRNAs (miRNAs) in the progression and management of the inflammatory response in intestinal diseases. Moreover, miRNAs are able to regulate expression of molecular mediators that are linking inflammation and cancer. In this work a miRNA panel differentially expressed between healthy, inflammatory bowel disease (IBD) and CC tissue was established. Identified miRNAs regulate signaling pathways related to inflammation and cancer progression. An inflammation associated-miRNA panel composed of 11-miRNAs was found to be overexpressed in CC but not in inflamed or normal tissues (miR-21-5p, miR-304-5p, miR-577, miR-335-5p, miR-21-3p, miR-27b-5p, miR-335-3p, miR-215-5p, miR-30b-5p, miR-192-5p, miR-3065-5p). The association of top hit miRNAs, miR-3065-5p and miR-30b-5p expression with overall survival of CC patients was demonstrated using Kaplan-Meier tests. Finally, differential miRNA expression was validated using an inflammation-associated CC model induced by Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) to compare miRNA expression in normal and inflamed tissue versus CC tissues. Based on these findings we propose the identified inflammatory miRNA panel as a potent diagnostic tool for CC determination.
A miRNA group distinguishes colon cancer tissues, since early stages, from inflamed or healthy colon tissues. The miRNA panel regulates signaling pathways related to cancer progression. The levels of pro-inflammatory cytokines are regulated by the miRNAs of the panel. Inflammation-related miRNAs are colon cancer prognosis biomarkers. A miRNA signature is specific biomarker for colitis-associated colon carcinogenesis.
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Affiliation(s)
| | - Berenice Carbajal-Lopez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
- Programa de Doctorado en Investigación en Medicina, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico
| | - Triet M. Bui
- Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St., Chicago, IL, 60611, USA
| | - Monica Mendoza-Rodriguez
- Unidad de Biomedicina, FES-Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Estado de México, 54090, Mexico
| | | | | | - David Cantú-De Leon
- Unidad de Investigación en Cáncer, Instituto Nacional de Cancerología, Tlalpan, Mexico
| | - Eduardo-Osiris Madrigal-Santillán
- Laboratorio de Medicina de la Conservación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Ciudad de México, 11340, Mexico
| | - Ronen Sumagin
- Department of Pathology, Northwestern University Feinberg School of Medicine, 300 East Superior St., Chicago, IL, 60611, USA
| | - Carlos Pérez-Plasencia
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
- Laboratorio de Genómica Funcional. Unidad de Biomedicina, FES-IZTACALA, UNAM, Tlalnepantla, Mexico
- Corresponding author. Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico.
| | - Eloy-Andrés Pérez-Yépez
- Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico
- Cátedra-CONACYT, Dirección de Cátedras, Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico
- Corresponding author. Laboratorio de Genómica, Instituto Nacional de Cancerología, Tlalpan, Mexico.
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11
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Huang Y, Zhang X, PengWang, Li Y, Yao J. Identification of hub genes and pathways in colitis-associated colon cancer by integrated bioinformatic analysis. BMC Genom Data 2022; 23:48. [PMID: 35733095 PMCID: PMC9219145 DOI: 10.1186/s12863-022-01065-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 06/13/2022] [Indexed: 12/25/2022] Open
Abstract
Background Colitis-associated colon cancer (CAC) patients have a younger age of onset, more multiple lesions and invasive tumors than sporadic colon cancer patients. Early detection of CAC using endoscopy is challenging, and the incidence of septal colon cancer remains high. Therefore, identifying biomarkers that can predict the tumorigenesis of CAC is in urgent need. Results A total of 275 DEGs were identified in CAC. IGF1, BMP4, SPP1, APOB, CCND1, CD44, PTGS2, CFTR, BMP2, KLF4, and TLR2 were identified as hub DEGs, which were significantly enriched in the PI3K-Akt pathway, stem cell pluripotency regulation, focal adhesion, Hippo signaling, and AMPK signaling pathways. Sankey diagram showed that the genes of both the PI3K-AKT signaling and focal adhesion pathways were upregulated (e.g., SPP1, CD44, TLR2, CCND1, and IGF1), and upregulated genes were predicted to be regulated by the crucial miRNAs: hsa-mir-16-5p, hsa-mir-1-3p, et al. Hub gene-TFs network revealed FOXC1 as a core transcription factor. In ulcerative colitis (UC) patients, KLF4, CFTR, BMP2, TLR2 showed significantly lower expression in UC-associated cancer. BMP4 and IGF1 showed higher expression in UC-Ca compared to nonneoplastic mucosa. Survival analysis showed that the differential expression of SPP1, CFRT, and KLF4 were associated with poor prognosis in colon cancer. Conclusion Our study provides novel insights into the mechanism underlying the development of CAC. The hub genes and signaling pathways may contribute to the prevention, diagnosis and treatment of CAC. Supplementary Information The online version contains supplementary material available at 10.1186/s12863-022-01065-7.
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Affiliation(s)
- Yongming Huang
- Department of General Surgery, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong Province, China
| | - Xiaoyuan Zhang
- Key Laboratory of Precision Oncology in Universities of Shandong, Department of Pathology and Institute of Precision Medicine, Taibai Lake New Area, Jining Medical University, 133 Hehua Road, Jining, 272067, Shandong Province, China
| | - PengWang
- Department of General Surgery, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong Province, China
| | - Yansen Li
- Department of General Surgery, Affiliated Hospital of Jining Medical University, 89 Guhuai Road, Jining, 272000, Shandong Province, China
| | - Jie Yao
- Department of Oncology, Jining Hospital of Traditional Chinese Medicine, 3 Huancheng North Road, Jining, 272000, Shandong Province, China.
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12
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Mohamadzade Z, Hasannia Kolagar T, Nemati H, Javanmard A, Soltani BM. Molecular and cellular evidence for hsa‐miR‐1254 suppressor effect against HER2 signaling in breast cancer. J Cell Biochem 2022; 123:746-758. [DOI: 10.1002/jcb.30218] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 10/24/2021] [Accepted: 01/10/2022] [Indexed: 01/18/2023]
Affiliation(s)
- Zahra Mohamadzade
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Tabssom Hasannia Kolagar
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Hossein Nemati
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Amir‐Reza Javanmard
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
| | - Bahram M. Soltani
- Department of Molecular Genetics, Faculty of Biological Sciences Tarbiat Modares University Tehran Iran
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13
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Zhou N, Yao Y, Wu N, Du H, Xu M, Zhao Y, Tu Y. VF-4 and DR-8 Derived from Salted Egg White Inhibit Inflammatory Activity via NF-κB/PI3K-Akt/MAPK Signal Transduction Pathways in HT-29 Cells Induced by TNF-α. Mol Nutr Food Res 2021; 66:e2100682. [PMID: 34821458 DOI: 10.1002/mnfr.202100682] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/04/2021] [Indexed: 12/11/2022]
Abstract
SCOPE Inflammation is the pathological basis of many chronic diseases, and persistent intestinal inflammation is a key factor in the further development of colon cancer. Egg-derived peptides have been proven to have anti-intestinal inflammation activity. Egg white treated with salt contains a lot of rich protein, whether its peptides have anti-inflammatory activity and how their mechanism of action is still unclear. METHODS AND RESULTS In this study, ELISA is used to determine the anti-inflammatory activity of the peptides (VF-4 and DR-8 from salted egg white), and then RNA-seq is used to explore the mechanism of their anti-inflammatory activity, and then verified by western blotting and inhibitors. The results show that VF-4 and DR-8 significantly inhibit TNF-α-induced IL-8 secretion in HT-29 cells in a concentration-dependent manner, and VF-4 show a more significant anti-inflammatory effect than DR-8. The anti-inflammatory mechanism of VF-4 and DR-8 is through inhibiting the activation of Nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and phosphatidylinositol 3' -kinase(PI3K)-Akt pathways, reducing the production of inflammatory mediators. CONCLUSION VF-4 and DR-8 have obvious anti-inflammatory activity, which can reduce intestinal inflammation and inhibit its further development into colon cancer.
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Affiliation(s)
- Na Zhou
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Yao Yao
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Na Wu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Huaying Du
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Mingsheng Xu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Yan Zhao
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
| | - Yonggang Tu
- Jiangxi Key Laboratory of Natural Products and Functional Food, Jiangxi Agricultural University, Nanchang, 330045, China.,Agricultural Products Processing and Quality Control Engineering Laboratory of Jiangxi, Jiangxi Agricultural University, Nan Chang, 330045, China
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14
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Insulin Resistance and Cancer: In Search for a Causal Link. Int J Mol Sci 2021; 22:ijms222011137. [PMID: 34681797 PMCID: PMC8540232 DOI: 10.3390/ijms222011137] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.
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15
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Park GB, Jeong JY, Kim D. GLUT5 regulation by AKT1/3-miR-125b-5p downregulation induces migratory activity and drug resistance in TLR-modified colorectal cancer cells. Carcinogenesis 2021; 41:1329-1340. [PMID: 32649737 DOI: 10.1093/carcin/bgaa074] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 05/26/2020] [Accepted: 07/08/2020] [Indexed: 12/16/2022] Open
Abstract
In cancer, resistance to chemotherapy is one of the main reasons for therapeutic failure. Cells that survive after treatment with anticancer drugs undergo various changes, including in cell metabolism. In this study, we investigated the effects of AKT-mediated miR-125b-5p alteration on metabolic changes and examined how these molecules enhance migration and induce drug resistance in colon cancer cells. AKT1 and AKT3 activation in drug-resistant colon cancer cells caused aberrant downregulation of miR-125b-5p, leading to GLUT5 expression. Targeted inhibition of AKT1 and AKT3 restored miR-125b-5p expression and prevented glycolysis- and lipogenesis-related enzyme activation. In addition, restoring the level of miR-125b-5p by transfection with the mimic sequence not only significantly blocked the production of lactate and intracellular fatty acids but also suppressed the migration and invasion of chemoresistant colon cancer cells. GLUT5 silencing with small interfering RNA attenuated mesenchymal marker expression and migratory activity in drug-resistant colon cancer cells. Additionally, treatment with 2,5-anhydro-d-mannitol resensitized chemoresistant cancer cells to oxaliplatin and 5-fluorouracil. In conclusion, our findings suggest that changes in miR-125b-5p and GLUT5 expression after chemotherapy can serve as a new marker to indicate metabolic change-induced migration and drug resistance development.
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Affiliation(s)
- Ga-Bin Park
- Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Kosin University College of Medicine, Busan, Republic of Korea
| | - Daejin Kim
- Department of Anatomy, Inje University College of Medicine, Busan, Republic of Korea
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16
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Khan P, Ebenezer NS, Siddiqui JA, Maurya SK, Lakshmanan I, Salgia R, Batra SK, Nasser MW. MicroRNA-1: Diverse role of a small player in multiple cancers. Semin Cell Dev Biol 2021; 124:114-126. [PMID: 34034986 DOI: 10.1016/j.semcdb.2021.05.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 05/07/2021] [Accepted: 05/16/2021] [Indexed: 12/12/2022]
Abstract
The process of cancer initiation and development is a dynamic and complex mechanism involving multiple genetic and non-genetic variations. With the development of high throughput techniques like next-generation sequencing, the field of cancer biology extended beyond the protein-coding genes. It brought the functional role of noncoding RNAs into cancer-associated pathways. MicroRNAs (miRNAs) are one such class of noncoding RNAs regulating different cancer development aspects, including progression and metastasis. MicroRNA-1 (miR-1) is a highly conserved miRNA with a functional role in developing skeletal muscle precursor cells and cardiomyocytes and acts as a consistent tumor suppressor gene. In humans, two discrete genes, MIR-1-1 located on 20q13.333 and MIR-1-2 located on 18q11.2 loci encode for a single mature miR-1. Downregulation of miR-1 has been demonstrated in multiple cancers, including lung, breast, liver, prostate, colorectal, pancreatic, medulloblastoma, and gastric cancer. A vast number of studies have shown that miR-1 affects the hallmarks of cancer like proliferation, invasion and metastasis, apoptosis, angiogenesis, chemosensitization, and immune modulation. The potential therapeutic applications of miR-1 in multiple cancer pathways provide a novel platform for developing anticancer therapies. This review focuses on the different antitumorigenic and therapeutic aspects of miR-1, including how it regulates tumor development and associated immunomodulatory functions.
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Affiliation(s)
- Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Nivetha Sarah Ebenezer
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Jawed Akhtar Siddiqui
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Shailendra Kumar Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Imayavaramban Lakshmanan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center and Beckman Research Institute, Duarte, CA 91010, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA; Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
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17
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Cell specific tumor suppressor effect of Hsa-miR-1226-3p through downregulation of HER2, PIK3R2, and AKT1 genes. Int J Biochem Cell Biol 2021; 134:105965. [DOI: 10.1016/j.biocel.2021.105965] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2020] [Revised: 01/19/2021] [Accepted: 03/01/2021] [Indexed: 12/21/2022]
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18
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Wang Y, Wang S, He JH. Transcriptomic analysis reveals essential microRNAs after peripheral nerve injury. Neural Regen Res 2021; 16:1865-1870. [PMID: 33510094 PMCID: PMC8328748 DOI: 10.4103/1673-5374.306092] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Studies have shown that microRNAs (miRNAs) mediate posttranscriptional regulation of target genes and participate in various physiological and pathological processes, including peripheral nerve injury. However, it is hard to select key miRNAs with essential biological functions among a large number of differentially expressed miRNAs. Previously, we collected injured sciatic nerve stumps at multiple time points after nerve crush injury, examined gene changes at different stages (acute, sub-acute, and post-acute), and obtained mRNA expression profiles. Here, we jointly analyzed mRNAs and miRNAs, and investigated upstream miRNAs of differentially expressed mRNAs using Ingenuity Pathway Analysis bioinformatic software. A total of 31, 42, 30, and 23 upstream miRNAs were identified at 1, 4, 7, and 14 days after rat sciatic nerve injury, respectively. Temporal expression patterns and biological involvement of commonly involved upstream miRNAs (miR-21, let-7, miR-223, miR-10b, miR-132, miR-15b, miR-127, miR-29a, miR-29b, and miR-9) were then determined at multiple time points. Expression levels of miR-21, miR-132, miR-29a, and miR-29b were robustly increased after sciatic nerve injury. Biological processes involving these miRNAs include multicellular organismal response to stress, positive regulation of the epidermal growth factor receptor signaling pathway, negative regulation of epithelial cell differentiation, and regulation of myocardial tissue growth. Moreover, we constructed mechanistic networks of let-7, miR-21, and miR-223, the most significantly involved upstream miRNAs. Our findings reveal that multiple upstream miRNAs (i.e., let-7, miR-21, and miR-223) were associated with gene expression changes in rat sciatic nerve stumps after nerve injury, and these miRNAs play an important role in peripheral nerve regeneration. This study was approved by the Experimental Animal Ethics Committee of Jiangsu Province of China (approval No. 20190303-18) on March 3, 2019.
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Affiliation(s)
- Yu Wang
- Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Shu Wang
- Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
| | - Jiang-Hong He
- Key Laboratory for Neuroregeneration of Jiangsu Province and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China
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19
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Catellani C, Ravegnini G, Sartori C, Angelini S, Street ME. GH and IGF System: The Regulatory Role of miRNAs and lncRNAs in Cancer. Front Endocrinol (Lausanne) 2021; 12:701246. [PMID: 34484116 PMCID: PMC8415755 DOI: 10.3389/fendo.2021.701246] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022] Open
Abstract
Growth hormone (GH) and the insulin-like growth factor (IGF) system are involved in many biological processes and have growth-promoting actions regulating cell proliferation, differentiation, apoptosis and angiogenesis. A recent chapter in epigenetics is represented by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) which regulate gene expression. Dysregulated miRNAs and lncRNAs have been associated with several diseases including cancer. Herein we report the most recent findings concerning miRNAs and lncRNAs regulating GH and the IGF system in the context of pituitary adenomas, osteosarcoma and colorectal cancer, shedding light on new possible therapeutic targets. Pituitary adenomas are increasingly common intracranial tumors and somatotroph adenomas determine supra-physiological GH secretion and cause acromegaly. Osteosarcoma is the most frequent bone tumor in children and adolescents and was reported in adults who were treated with GH in childhood. Colorectal cancer is the third cancer in the world and has a higher prevalence in acromegalic patients.
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Affiliation(s)
- Cecilia Catellani
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- PhD Program in Clinical and Experimental Medicine, University of Modena and Reggio Emilia, Modena, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Chiara Sartori
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, University of Bologna, Bologna, Italy
| | - Maria E. Street
- Department of Mother and Child, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy
- *Correspondence: Maria E. Street,
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20
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Zhu T, Chen Y, Liu Z, Leng Y, Tian Y. Expression profiles and prognostic significance of AFTPH in different tumors. FEBS Open Bio 2020; 10:2666-2677. [PMID: 33090728 PMCID: PMC7714068 DOI: 10.1002/2211-5463.13003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 08/24/2020] [Accepted: 09/23/2020] [Indexed: 01/16/2023] Open
Abstract
Aftiphilin (AFTPH) plays an important role in regulating intracellular trafficking, exocytosis, and the pro‐inflammatory response. However, the potential prognostic role of AFTPH in cancers remains unclear. Here, we examined the expression profiles and prognostic significance of AFTPH in breast invasive carcinoma (BRCA), diffuse large B‐cell lymphoma (DLBC), lung squamous cell carcinoma (LUSC), and pancreatic adenocarcinoma (PADD) using the GEPIA and UALCAN databases. AFTPH expression was observed to be higher in cancer tissues than in normal tissues, but expression did not differ significantly between tumor stages for the four cancer types. AFTPH expression in cancer cell lines was investigated using the CCLE database; AFTPH was found to be highly expressed in four cancer cell lines. The relationship between AFTPH expression and patient prognosis was analyzed using GEPIA, LinkedOmics, and Kaplan–Meier plotter databases. Low expression of AFTPH was associated with improved prognosis for BRCA, DLBC, LUSC, and PAAD. Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD. Related genes and markers associated with AFTPH were discovered using the LinkedOmics database. Furthermore, transfection of cells with AFTPH siRNA demonstrated that AFTPH exerts positive effects on cell proliferation in BRCA, LUSC, and PAAD cells. In conclusion, AFTPH may be a potential therapeutic target and prognostic biomarker for BRCA, DLBC, LUSC, and/or PAAD.
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Affiliation(s)
- Tengjiao Zhu
- Third Hospital of Peking University, Beijing, China
| | | | - Zhongjun Liu
- Third Hospital of Peking University, Beijing, China
| | - Yuxin Leng
- Third Hospital of Peking University, Beijing, China
| | - Yun Tian
- Third Hospital of Peking University, Beijing, China
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Jänicke P, Lennicke C, Meister A, Seliger B, Wessjohann LA, Kaluđerović GN. Fluorescent spherical mesoporous silica nanoparticles loaded with emodin: Synthesis, cellular uptake and anticancer activity. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2020; 119:111619. [PMID: 33321661 DOI: 10.1016/j.msec.2020.111619] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 09/24/2020] [Accepted: 10/07/2020] [Indexed: 12/14/2022]
Abstract
The natural product emodin (EO) exhibits anti-inflammatory, antiangiogenesis and antineoplastic properties in vitro and in vivo. Due to its biological properties as well as its fluorescence, EO can be useful in pharmacology and pharmacokinetics. To enhance its selectivity to cancer cells, EO was loaded into non-fluorescent and novel fluorescent spherical mesoporous nanoparticles bearing N-methyl isatoic anhydride (SNM~M) or lissamine rhodamine B sulfonyl moieties (SNM~L). The propylamine functionalized mesoporous silica nanomaterial (SNM) were characterized by powder X-ray diffraction (XRD), nitrogen gas sorption, scanning electron microscopy (SEM), transmission electron microscopy (TEM), fluorescence spectroscopy, thermogravimetric analysis (TGA) and UV spectroscopy. The cytotoxicity of EO-loaded nanoparticles was tested against the human colon carcinoma cell line HT-29. Non-loaded SNM did not affect cell proliferation, whereas those loaded with EO were at least as efficient as EO alone. It could be shown by fluorescence microscopy that the uptake of silica nanomaterial by the tumor cells occurred within 2 h and the release of EO occurred within 48 h of treatment. Flow cytometry and Western blot analysis showed that SNM containing EO induced apoptosis in HT-29 cells.
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Affiliation(s)
- Paul Jänicke
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D 06120 Halle (Saale), Germany
| | - Claudia Lennicke
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, D 06112 Halle (Saale), Germany
| | - Annette Meister
- Institute for Chemistry - Physical and Theoretical Chemistry, Martin Luther University Halle-Wittenberg, D 06099 Halle (Saale), Germany
| | - Barbara Seliger
- Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, D 06112 Halle (Saale), Germany
| | - Ludger A Wessjohann
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D 06120 Halle (Saale), Germany
| | - Goran N Kaluđerović
- Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, D 06120 Halle (Saale), Germany; Department of Engineering and Natural Sciences, University of Applied Sciences Merseburg, Eberhard-Leibnitz-Straße 2, 06217 Merseburg, Germany.
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22
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Mohamadzade Z, Mahjoubi F, Soltani BM. Introduction of hsa-miR-512-3p as a new regulator of HER2 signaling pathway in breast cancer. Breast Cancer Res Treat 2020; 185:95-106. [PMID: 32974790 DOI: 10.1007/s10549-020-05937-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Accepted: 09/12/2020] [Indexed: 11/28/2022]
Abstract
PURPOSE Dysregulation of HER2 signaling pathway in breast cancer is well documented. Our bioinformatics analysis predicted hsa-miR-512-3p (miR-512-3p) as a bona fide regulator of HER2 as well as HER3, PIK3R2, and AKT1 genes. Then, we intended to examine the effect of miR-512-3p on the predicted target genes that are involved in HER2 signaling pathway. METHODS AND RESULTS RT-qPCR results indicated lower expression of miR-512-3p in breast cancer specimens, compared to their normal pairs. Overexpression of miR-512-3p resulted in HER2, HER3, PIK3R2, and AKT1 gene downregulation, detected by RT-qPCR and the result was confirmed by western analysis and ELIZA test against p-AKT, BAX, FADD, and HER2 proteins in SKBR3 cells, respectively. Then, dual-luciferase assay supported the direct interaction of miR-512-3p with 3'UTR sequences of HER2, HER3, PIK3R2, and AKT1 target genes. When miR-512-3p was overexpressed, BAX/BCL2 expression ratio and proportion of sub-G1 cell population were increased in transfected SKBR3 cells, detected by RT-qPCR and flow cytometry, respectively. These results were consistent with the decreased viability of transfected cells, documented by MTT assay. In addition, results were consistent with the upregulation of BAX, BAK, BOK, PTEN, P53, and P21 genes and downregulation of CCND1 gene in SKBR3 cells. Although the overexpression of miR-512 resulted in cell cycle arrest at Sub-G1 stage in MDA-MB-231 cells, this effect seemed independent of targeting HER2, HER3, PIK3R2, and AKT1 target genes. CONCLUSION Overall, results indicated that miR-512-3p acts as a cell-type-specific tumor suppressor, through targeting HER2, HER3, PIK3R2, and AKT1 transcripts. These results suggest miR-512-3p as a potential candidate marker for breast cancer diagnosis.
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Affiliation(s)
- Zahra Mohamadzade
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 111-14115, Iran
| | - Frouzande Mahjoubi
- Clinical Genetic Department, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
| | - Bahram M Soltani
- Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, 111-14115, Iran.
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Osteoclast signaling-targeting miR-146a-3p and miR-155-5p are downregulated in Paget's disease of bone. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165852. [PMID: 32485219 DOI: 10.1016/j.bbadis.2020.165852] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 05/25/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022]
Abstract
MicroRNA (miRs) are small, non-coding RNA that post-transcriptionally regulate DNA expression. We hypothesized that specific miR profiles may be a feature of overactive osteoclasts in Paget's disease of bone (PDB), a disorder characterized by an increased and disorganized bone remodeling that typically begins with excessive bone resorption. We compared the expression profile of 13 miRs in human osteoclasts differentiated in vitro from peripheral blood mononuclear cells (PBMCs) of patients with PDB (n = 10) or age- and sex- matched healthy subjects (n = 10). We selected 13 miRs for testing, on the basis of their previously reported roles either in human osteoclast differentiation, in bone diseases, or in osteoclast important signaling pathways. From those expression results, 3 miRNAs were further selected for in-vitro studies aiming at modulating miR expression in human cord blood monocyte derived osteoclasts: 2 miRs (miR-146a-3p and miR-155-5p) whose expression was significantly reduced in pagetic osteoclasts, as well as miRNA-133a-3p, stable in PDB relative to controls, but with known regulatory importance within osteoclasts. We demonstrated a positive (miR-133a-3p) or negative (miR-155-5p, miR-146a-3p) impact of those miRs on the formation of osteoclasts and/or their bone resorption capacity in this human model. Signaling pathways were significantly affected, including p38 MAP-kinase (miR-133a-3p), RANKL-induced TRAF6/NFκB signaling (miR-146a-3p), and MITF expression (miR-155-5p). Osteoclast miRNA profiles might have an important value to yield significant new insights into the osteoclast phenotype in PDB and in other bone diseases with hyperactive osteoclasts.
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24
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Chen B, Li J, Chi D, Sahnoune I, Calin S, Girnita L, Calin GA. Non-Coding RNAs in IGF-1R Signaling Regulation: The Underlying Pathophysiological Link between Diabetes and Cancer. Cells 2019; 8:cells8121638. [PMID: 31847392 PMCID: PMC6953109 DOI: 10.3390/cells8121638] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/06/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022] Open
Abstract
The intricate molecular network shared between diabetes mellitus (DM) and cancer has been broadly understood. DM has been associated with several hormone-dependent malignancies, including breast, pancreatic, and colorectal cancer (CRC). Insulin resistance, hyperglycemia, and inflammation are the main pathophysiological mechanisms linking DM to cancer. Non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are widely appreciated as pervasive regulators of gene expression, governing the evolution of metabolic disorders, including DM and cancer. The ways ncRNAs affect the development of DM complicated with cancer have only started to be revealed in recent years. Insulin-like growth factor 1 receptor (IGF-1R) signaling is a master regulator of pathophysiological processes directing DM and cancer. In this review, we briefly summarize a number of well-known miRNAs and lncRNAs that regulate the IGF-1R in DM and cancer, respectively, and further discuss the potential underlying molecular pathogenesis of this disease association.
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Affiliation(s)
- Baoqing Chen
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA;
- Correspondence: (B.C.); (G.A.C.)
| | - Junyan Li
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;
| | - Dongmei Chi
- Department of Anesthesiology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China;
| | - Iman Sahnoune
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA;
| | - Steliana Calin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA;
| | - Leonard Girnita
- Department of Oncology-Pathology, Cellular and Molecular Tumor Pathology, Karolinska Institute, 17164 Stockholm, Sweden;
| | - George A. Calin
- Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA;
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Correspondence: (B.C.); (G.A.C.)
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Oral Administration of Microencapsulated B. Longum BAA-999 and Lycopene Modulates IGF-1/IGF-1R/IGFBP3 Protein Expressions in a Colorectal Murine Model. Int J Mol Sci 2019; 20:ijms20174275. [PMID: 31480481 PMCID: PMC6747182 DOI: 10.3390/ijms20174275] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 08/24/2019] [Accepted: 08/29/2019] [Indexed: 01/09/2023] Open
Abstract
The Insulin-like growth factor-I/Insulin-like growth factor-I receptor (IGF-1/IGF-1R) system is a major determinant in colorectal cancer (CRC) pathogenesis. Probiotics (Bifidobacterium longum, BF) and lycopene (LYC) have been individually researched for their beneficial effects in the prevention of CRC. However, the effect of a combined treatment of microencapsulated BF and LYC on IGF-1/IGF-1R/IGFBPs (Insulin-like growth factor-binding proteins) expression in an azoxymethane (AOM)-dextran sulfate sodium (DSS)-induced CRC model have not been demonstrated. BF was microencapsulated by the spray drying technique, with high viability, and daily gavaged with LYC for 16 weeks to CD-1 mice in an AOM-DSS model. The results indicated that BF- and BF + LYC-treated groups had significantly lower inflammation grade, tumor incidence (13–38%) and adenocarcinoma (13–14%) incidence compared to the AOM + DSS group (80%), whereas LYC treatment only protected against inflammation grade and incidence. Caecal, colonic and fecal pH and β-glucuronidase (β-GA) values were significantly normalized by BF and LYC. Similarly, BF and BF + LYC treatments significantly reduced both the positive rate and expression grade of IGF-1 and IGF-1R proteins and normalized Insulin-like growth factor-binding protein-3 (IGFBP3) expression. Based on intestinal parameters related to the specific colon carcinogenesis in an AOM-DSS-induced model, LYC and microencapsulated BF supplementation resulted in a significant chemopreventive potential through the modulation of IGF-1/IGF-1R system.
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26
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Yuan L, Fan L, Li Q, Cui W, Wang X, Zhang Z. Inhibition of miR‐181b‐5p protects cardiomyocytes against ischemia/reperfusion injury by targeting AKT3 and PI3KR3. J Cell Biochem 2019; 120:19647-19659. [PMID: 31297863 DOI: 10.1002/jcb.29271] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 04/08/2019] [Indexed: 12/30/2022]
Affiliation(s)
- Limei Yuan
- College of Acupuncture and Message Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Lihua Fan
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Qinghai Li
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Wei Cui
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Xuechen Wang
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
| | - Zhiguo Zhang
- Departement of Cardiovascular Third Affiliated Hospital of Henan University of Traditional Chinese Medicine Zhengzhou Henan Province China
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27
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Heydari Z, Rahaie M, Alizadeh AM. Different anti-inflammatory effects of Lactobacillus acidophilus and Bifidobactrum bifidioum in hepatocellular carcinoma cancer mouse through impact on microRNAs and their target genes. JOURNAL OF NUTRITION & INTERMEDIARY METABOLISM 2019. [DOI: 10.1016/j.jnim.2019.100096] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Wu YQ, Ju CL, Wang BJ, Wang RG. PABPC1L depletion inhibits proliferation and migration via blockage of AKT pathway in human colorectal cancer cells. Oncol Lett 2019; 17:3439-3445. [PMID: 30867782 PMCID: PMC6396114 DOI: 10.3892/ol.2019.9999] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 01/22/2019] [Indexed: 12/20/2022] Open
Abstract
Numerous studies have demonstrated that PABPC1 participates in the process of carcinogenesis and its function is inconsistent in different types of cancers. PABPC1-like (PABPC1L) is an important paralog of PABPC1 and few studies are available on the roles of PABPC1L in colorectal cancer (CRC) development. Hence, we explored the biological function and prognostic impact of PABPC1L in CRC. The mRNA expression of PABPC1L in CRC was determined based on the data obtained from The Cancer Genome Atlas (TCGA) database. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was utilized to determine the PABPC1L mRNA expression level in CRC HT-29 and LS-174T cell lines. Kaplan-Meier method and Cox proportional-hazards model were utilized to conduct the survival and prognosis analyses. HT-29 cells with silenced PABPC1L were constructed to explore the effect of PABPC1L on cell proliferation, invasion and migration capacities using cell counting kit-8 (CCK-8), clone formation, wound-healing and Transwell assays, respectively. To uncover the potential mechanisms of how PABPC1L influences CRC proliferation and migration, we analyzed the expression of AKT, p-AKT, PI3K, and p-PI3K in HT-29 cells using western blotting. Our results revealed that PABPC1L was overexpressed in CRC tissues compared with normal tissues based on the data obtained from TCGA database. Similarly, the mRNA expression of PABPC1L was higher in HT-29 and LS-174T cells than that in CCD-18Co cells. The expression of PABPC1L in CRC was found to be significantly related to age, pathologic stage, pathologic-node, pathologic-metastasis, and death. In univariate and multivariate analyses, pathologic-tumor and pathologic-metastasis were identified as independent prognostic factors for CRC. After PABPC1L depletion, cell proliferation rate, colony numbers, and the invasive and migratory capacity of HT-29 cells were all reduced. Western blot analysis showed that reduction of PABPC1L significantly inhibited p-AKT, and p-PI3K expression level in HT-29 cells. Collectively, our results suggested that PABPC1L is a potential novel candidate oncogene in CRC, and targeting PABPC1L may provide clinical utility in CRC.
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Affiliation(s)
- Yue-Qin Wu
- Department of Integration of Traditional Chinese Medicine and Western Medicine, Tianjin First Central Hospital, Tianjin 300192, P.R. China
| | - Chao-Long Ju
- Anorectal Department of Traditional Chinese Medicine, Central Hospital of Tongchuan Mining Bureau, Tongchuan, Shanxi 727000, P.R. China
| | - Bao-Juan Wang
- Department of Nephropathy, The Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300150, P.R. China
| | - Ruo-Gu Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Shandong Academy of Medical Sciences, Jinan, Shandong 250031, P.R. China
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Li H, Li SJ, Shang J, Liu JX, Zheng CH. A Dynamic Scale-Free Network Particle Swarm Optimization for Extracting Features on Multi-Omics Data. J Comput Biol 2018; 26:769-781. [PMID: 30495971 DOI: 10.1089/cmb.2018.0185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Mining meaningful and comprehensive molecular characterization of cancers from The Cancer Genome Atlas (TCGA) data has become a bioinformatics bottleneck. Meanwhile, recent progress in cancer analysis shows that multi-omics data can effectively and systematically detect the cancer-related genes at all levels. In this study, we propose an improved particle swarm optimization with dynamic scale-free network, named DSFPSO, to extract features on multi-omics data. The highlights of DSFPSO are taking the dynamic scale-free network as its population structure and diverse velocity updating strategies for fully considering the heterogeneity of particles and their neighbors. Experiments of DSFPSO and its comparison with several state-of-the-art feature extraction approaches are performed on two public data sets from TCGA. Results show that DSFPSO can extract genes associated with cancers effectively.
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Affiliation(s)
- Huiyu Li
- 1School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Sheng-Jun Li
- 1School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Junliang Shang
- 1School of Information Science and Engineering, Qufu Normal University, Rizhao, China.,2School of Statistics, Qufu Normal University, Qufu, China
| | - Jin-Xing Liu
- 1School of Information Science and Engineering, Qufu Normal University, Rizhao, China
| | - Chun-Hou Zheng
- 3School of Computer Science and Technology, Anhui University, Hefei, China
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Lyophilized açaí pulp (Euterpe oleracea Mart) attenuates colitis-associated colon carcinogenesis while its main anthocyanin has the potential to affect the motility of colon cancer cells. Food Chem Toxicol 2018; 121:237-245. [DOI: 10.1016/j.fct.2018.08.078] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 08/24/2018] [Accepted: 08/31/2018] [Indexed: 12/21/2022]
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Trotta MC, Maisto R, Alessio N, Hermenean A, D'Amico M, Di Filippo C. The Melanocortin MC5R as a New Target for Treatment of High Glucose-Induced Hypertrophy of the Cardiac H9c2 Cells. Front Physiol 2018; 9:1475. [PMID: 30416452 PMCID: PMC6212602 DOI: 10.3389/fphys.2018.01475] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 09/28/2018] [Indexed: 12/15/2022] Open
Abstract
The study explored the anti-hypertrophic effect of the melanocortin MC5R stimulation in H9c2 cardiac myocytes exposed to high glucose. This has been done by using α-MSH and selective MC5R agonists and assessing the expression of GLUT4 and GLUT1 transporters, miR-133 and urotensin receptor levels as a marker of cardiac hypertrophy. The study shows for the first time an up-regulation of MC5R expression levels in H9c2 cardiomyocytes exposed to high glucose medium (33 mM D-glucose) for 48 h, compared to cells grown in normal glucose medium (5.5 mM D-glucose). Moreover, H9c2 cells exposed to high glucose showed a significant reduction in cell viability (-40%), a significant increase in total protein per cell number (+109%), and an increase of the urotensin receptor expression levels as an evidence of cells hypertrophy. The pharmacological stimulation of MC5R with α-MSH (90 pM)of the high glucose exposed H9c2 cells increased the cell survival (+50,8%) and reduced the total protein per cell number (-28,2%) with respect to high glucose alone, confirming a reduction of the hypertrophic state as per cell area measurement. Similarly, PG-901 (selective agonist, 10-10 M) significantly increased cell viability (+61,0 %) and reduced total protein per cell number (-40,2%), compared to cells exposed to high glucose alone. Interestingly, the MC5R agonist reduced the GLUT1/GLUT4 glucose transporters ratio on the cell membranes exhibited by the hypertrophic H9c2 cells and increased the intracellular PI3K activity, mediated by a decrease of the levels of the miRNA miR-133a. The beneficial effects of MC5R agonism on the cardiac hypertrophy caused by high glucose was also observed also by echocardiographic evaluations of rats made diabetics with streptozotocin (65 mg/kg i.p.). Therefore, the melanocortin MC5R could be a new target for the treatment of high glucose-induced hypertrophy of the cardiac H9c2 cells.
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Affiliation(s)
- Maria Consiglia Trotta
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Rosa Maisto
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Nicola Alessio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Anca Hermenean
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Arad, Romania
| | - Michele D'Amico
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Clara Di Filippo
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
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Yuan G, Chen T, Zhang H, Cao Q, Qiu Y, Que B, Peng S, Chen M, Ji W. Comprehensive analysis of differential circular RNA expression in a mouse model of colitis-induced colon carcinoma. Mol Carcinog 2018; 57:1825-1834. [PMID: 30182433 DOI: 10.1002/mc.22900] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 08/24/2018] [Accepted: 08/31/2018] [Indexed: 02/06/2023]
Abstract
Circular RNAs (circRNAs) have received increasing attention for their involvement in the pathogenesis of cancer; however, the characterization and function of circRNAs in colitis-induced colon carcinoma remains largely unknown. A colitis-induced colon carcinoma model was established in mice treated with azoxymethane-dextran sodium sulfate (AOM-DSS), and the circRNA profile was screened by next generation sequencing. Bioinformatic tools, including Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and network analysis were used to predict the functions of differentially expressed circRNAs and potentially coexpressed target genes. Among the detected candidate 3069 circRNA genes, 126 circRNAs were upregulated, and 108 circRNAs were down regulated in colon tissues from AOM/DSS mice compared to those from control mice. A total of six of these candidate circRNAs were validated by RT-PCR. GO analysis revealed that numerous target genes including most microRNAs were involved in the Ras-Raf-MAPK pathway, actin cytoskeleton, focal adhesion, and additional biological processes. Our study revealed a comprehensive expression and functional profile for differentially expressed circRNAs in AOM/DSS induced colon carcinogenesis, indicating possible involvement of these dysregulated circRNAs in the development of colitis-induced colon carcinoma. The mmu-circ-001226/mmu-circ-000287-miRNA-mRNA network may provide a potential mechanism for colitis-associated colorectal cancer.
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Affiliation(s)
- Gang Yuan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tingjia Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Haiqing Zhang
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qinghua Cao
- Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yun Qiu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Biao Que
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sui Peng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weidong Ji
- Center for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Extensive screening of microRNA populations identifies hsa-miR-375 and hsa-miR-133a-3p as selective markers for human rectal and colon cancer. Oncotarget 2018; 9:27256-27267. [PMID: 29930763 PMCID: PMC6007480 DOI: 10.18632/oncotarget.25535] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 04/28/2018] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNAs) are ∼22-nt molecules exerting control of protein expression in cancer tissues. The current study determined the full spectrum of miRNA dysregulation in freshly isolated human colon or rectal cancer biopsies as well as in controls of healthy adjacent tissue (total of n = 100) using an Illumina sequencing technology. In this work, we aimed to identify miRNAs that may serve as future marker to discern between these two subtypes. DESeq2 analysis revealed 53 significantly dysregulated miRNAs in colon cancer, 67 miRNAs in rectal cancer, and 97 miRNAs in both at a Padj value < 0.05 and ≥ 10 read counts. 65% of miRNAs were upregulated in colon as well as rectal cancer. Highest significant dysregulation (Padj < 0.00001) was detected for hsa-miR-21-5p, -215-5p and -378a in both colon and rectal cancer. Among the group of miRNAs with Padj < 0.05 and more than 2-fold expression differences, hsa-miR-375 was detected in rectal cancer only, and hsa-miR-133a-3p only in colon cancer. Receiver operating characteristic (ROC) analysis confirmed highly distinct sensitivities for hsa-miR-375 to detect rectal cancer (area under the curve (AUC): 0.9), while hsa-miR-133a-3p (AUC: 0.89) had the highest sensitivity for detecting colon cancer. We conclude that hsa-miR-375 and hsa-miR-133a-3p may serve as new markers of rectal or colon cancer and should be further investigated to search for different etiologies of colorectal cancer.
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Momen-Heravi F, Bala S. miRNA regulation of innate immunity. J Leukoc Biol 2018; 103:1205-1217. [PMID: 29656417 DOI: 10.1002/jlb.3mir1117-459r] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 02/15/2018] [Accepted: 02/25/2018] [Indexed: 12/17/2022] Open
Abstract
MicroRNAs (miRNAs) are small noncoding RNA and are pivotal posttranscriptional regulators of both innate and adaptive immunity. They act by regulating the expression of multiple immune genes, thus, are the important elements to the complex immune regulatory network. Deregulated expression of specific miRNAs can lead to potential autoimmunity, immune tolerance, hyper-inflammatory phenotype, and cancer initiation and progression. In this review, we discuss the contributory pathways and mechanisms by which several miRNAs influence the development of innate immunity and fine-tune immune response. Moreover, we discuss the consequence of deregulated miRNAs and their pathogenic implications.
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Affiliation(s)
- Fatemeh Momen-Heravi
- Division of Periodontics, Section of Oral and Diagnostic Sciences, Columbia University College of Dental Medicine, New York, New York, USA
| | - Shashi Bala
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Szymonowicz K, Oeck S, Malewicz NM, Jendrossek V. New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response. Cancers (Basel) 2018; 10:cancers10030078. [PMID: 29562639 PMCID: PMC5876653 DOI: 10.3390/cancers10030078] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2018] [Revised: 03/15/2018] [Accepted: 03/16/2018] [Indexed: 12/19/2022] Open
Abstract
Genetic alterations driving aberrant activation of the survival kinase Protein Kinase B (Akt) are observed with high frequency during malignant transformation and cancer progression. Oncogenic gene mutations coding for the upstream regulators or Akt, e.g., growth factor receptors, RAS and phosphatidylinositol-3-kinase (PI3K), or for one of the three Akt isoforms as well as loss of the tumor suppressor Phosphatase and Tensin Homolog on Chromosome Ten (PTEN) lead to constitutive activation of Akt. By activating Akt, these genetic alterations not only promote growth, proliferation and malignant behavior of cancer cells by phosphorylation of various downstream signaling molecules and signaling nodes but can also contribute to chemo- and radioresistance in many types of tumors. Here we review current knowledge on the mechanisms dictating Akt’s activation and target selection including the involvement of miRNAs and with focus on compartmentalization of the signaling network. Moreover, we discuss recent advances in the cross-talk with DNA damage response highlighting nuclear Akt target proteins with potential involvement in the regulation of DNA double strand break repair.
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Affiliation(s)
- Klaudia Szymonowicz
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45122 Essen, Germany.
| | - Sebastian Oeck
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45122 Essen, Germany.
- Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA.
| | - Nathalie M Malewicz
- Department of Anesthesiology, Yale University School of Medicine, New Haven, CT 06520, USA.
| | - Verena Jendrossek
- Institute of Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, 45122 Essen, Germany.
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Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), significantly increases the risk for development of colorectal cancer. Specifically, dysplasia and cancer associated with IBD (colitis-associated cancer or CAC) develop as a result of repeated cycles of injury and healing in the intestinal epithelium. Animal models are utilized to examine the mechanisms of CAC, the role of epithelial and immune cells in this process, as well as the development of novel therapeutic targets. These models typically begin with the administration of a carcinogenic compound, and inflammation is caused by repeated cycles of colitis-inducing agents. This review describes a common CAC model that utilizes the pro-carcinogenic compound azoxymethane (AOM) followed by dextran sulfate sodium (DSS) which induces the inflammatory insult.
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Toiyama Y, Okugawa Y, Tanaka K, Araki T, Uchida K, Hishida A, Uchino M, Ikeuchi H, Hirota S, Kusunoki M, Boland CR, Goel A. A Panel of Methylated MicroRNA Biomarkers for Identifying High-Risk Patients With Ulcerative Colitis-Associated Colorectal Cancer. Gastroenterology 2017; 153:1634-1646.e8. [PMID: 28847750 PMCID: PMC5748293 DOI: 10.1053/j.gastro.2017.08.037] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 07/27/2017] [Accepted: 08/18/2017] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Methylation of specific microRNAs (miRNAs) often occurs in an age-dependent manner, as a field defect in some instances, and may be an early event in colitis-associated carcinogenesis. We aimed to determine whether specific mRNA signature patterns (MIR1, MIR9, MIR124, MIR137, MIR34B/C) could be used to identify patients with ulcerative colitis (UC) who are at increased risk for colorectal neoplasia. METHODS We obtained 387 colorectal tissue specimens collected from 238 patients with UC (152 without neoplasia, 17 with dysplasia, and 69 with UC-associated colorectal cancer [UC-CRC]), from 2 independent cohorts in Japan between 2005 and 2015. We quantified methylation of miRNAs by bisulfite pyrosequencing analysis. We analyzed clinical data to determine whether miRNA methylation patterns were associated with age, location, or segment of the colorectum (cecum, transverse colon, and rectum). Differences in tissue miRNA methylation and expression levels were compared among samples and associated with cancer risk using the Wilcoxon, Mann-Whitney, and Kruskal-Wallis tests as appropriate. We performed a validation study of samples from 90 patients without UC and 61 patients with UC-associated dysplasia or cancer to confirm the association between specific methylation patterns of miRNAs in non-tumor rectal mucosa from patients with UC at risk of UC-CRC. RESULTS Among patients with UC without neoplasia, rectal tissues had significantly higher levels of methylation levels of MIR1, MIR9, MIR124, and MIR137 than in proximal mucosa; levels of methylation were associated with age and duration of UC in rectal mucosa. Methylation of all miRNAs was significantly higher in samples from patients with dysplasia or CRC compared with samples from patients without neoplasia. Receiver operating characteristic analysis revealed that methylation levels of miRNAs in rectal mucosa accurately differentiated patients with CRC from those without. Methylation of MIR137 in rectal mucosa was an independent risk factor for UC-CRC. Methylation patterns of a set of miRNAs (panel) could discriminate discriminate UC patients with or without dysplasia or CRC in the evaluation cohort (area under the curve, 0.81) and the validation cohort (area under the curve, 0.78). CONCLUSIONS In evaluation and validation cohorts, we found specific miRNAs to be methylated in rectal mucosal samples from patients with UC with dysplasia or CRC compared with patients without neoplasms. This pattern also associated with patient age and might be used to identify patients with UC at greatest risk for developing UC-CRC. Our findings provide evidence for a field defect in rectal mucosa from patients with UC-CRC.
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Affiliation(s)
- Yuji Toiyama
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Yoshinaga Okugawa
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Koji Tanaka
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Toshimitsu Araki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Keiichi Uchida
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - Asahi Hishida
- Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Motoi Uchino
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Hiroki Ikeuchi
- Department of Inflammatory Bowel Disease, Hyogo College of Medicine, Hyogo, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Hyogo, Japan
| | - Masato Kusunoki
- Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan
| | - C. Richard Boland
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas,School of Medicine, University of California, San Diego, La Jolla, California
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas.
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Slattery ML, Mullany LE, Sakoda LC, Wolff RK, Stevens JR, Samowitz WS, Herrick JS. The PI3K/AKT signaling pathway: Associations of miRNAs with dysregulated gene expression in colorectal cancer. Mol Carcinog 2017; 57:243-261. [PMID: 29068474 PMCID: PMC5760356 DOI: 10.1002/mc.22752] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 10/03/2017] [Accepted: 10/23/2017] [Indexed: 01/04/2023]
Abstract
The PI3K/AKT‐signaling pathway is one of the most frequently activated signal‐transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA‐Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of >1.5 or <0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of <0.67, and 57 had a FC of >1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed‐region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed‐region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR‐203a with ITGA4, miR‐6071 with ITGAV, and miR‐375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt‐signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.
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Affiliation(s)
- Martha L Slattery
- Department of Medicine, University of Utah, Colorow, Salt Lake City, Utah
| | - Lila E Mullany
- Department of Medicine, University of Utah, Colorow, Salt Lake City, Utah
| | - Lori C Sakoda
- Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Roger K Wolff
- Department of Medicine, University of Utah, Colorow, Salt Lake City, Utah
| | - John R Stevens
- Department of Mathematics and Statistics, Utah State University, Logan, Utah
| | - Wade S Samowitz
- Department of Pathology, University of Utah, Salt Lake City, Utah
| | - Jennifer S Herrick
- Department of Medicine, University of Utah, Colorow, Salt Lake City, Utah
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Law IKM, Padua DM, Iliopoulos D, Pothoulakis C. Role of G protein-coupled receptors-microRNA interactions in gastrointestinal pathophysiology. Am J Physiol Gastrointest Liver Physiol 2017; 313:G361-G372. [PMID: 28774868 PMCID: PMC5792214 DOI: 10.1152/ajpgi.00144.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Revised: 07/13/2017] [Accepted: 07/24/2017] [Indexed: 01/31/2023]
Abstract
G protein-coupled receptors (GPCRs) make up the largest transmembrane receptor superfamily in the human genome and are expressed in nearly all gastrointestinal cell types. Coupling of GPCRs and their respective ligands activates various phosphotransferases in the cytoplasm, and, thus, activation of GPCR signaling in intestine regulates many cellular and physiological processes. Studies in microRNAs (miRNAs) demonstrate that they represent critical epigenetic regulators of different pathophysiological responses in different organs and cell types in humans and animals. Here, we reviewed recent research on GPCR-miRNA interactions related to gastrointestinal pathophysiology, such as inflammatory bowel diseases, irritable bowel syndrome, and gastrointestinal cancers. Given that the presence of different types of cells in the gastrointestinal tract suggests the importance of cell-cell interactions in maintaining gastrointestinal homeostasis, we also discuss how GPCR-miRNA interactions regulate gene expression at the cellular level and subsequently modulate gastrointestinal pathophysiology through molecular regulatory circuits and cell-cell interactions. These studies helped identify novel molecular pathways leading to the discovery of potential biomarkers for gastrointestinal diseases.
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Affiliation(s)
- Ivy Ka Man Law
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - David Miguel Padua
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
| | - Dimitrios Iliopoulos
- 1Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and ,2Center for Systems Biomedicine, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Charalabos Pothoulakis
- Center for Inflammatory Bowel Diseases, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and
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Protein kinase B: emerging mechanisms of isoform-specific regulation of cellular signaling in cancer. Anticancer Drugs 2017; 28:569-580. [PMID: 28379898 DOI: 10.1097/cad.0000000000000496] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial-mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial-mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBβ (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance.
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Cardamonin inhibits colonic neoplasia through modulation of MicroRNA expression. Sci Rep 2017; 7:13945. [PMID: 29066742 PMCID: PMC5655681 DOI: 10.1038/s41598-017-14253-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Accepted: 10/09/2017] [Indexed: 12/19/2022] Open
Abstract
Colorectal cancer is currently the third leading cause of cancer related deaths. There is considerable interest in using dietary intervention strategies to prevent chronic diseases including cancer. Cardamonin is a spice derived nutraceutical and herein, for the first time we evaluated the therapeutic benefits of cardamonin in Azoxymethane (AOM) induced mouse model of colorectal cancer. Mice were divided into 4 groups of which three groups were given six weekly injections of AOM. One group served as untreated control and remaining groups were treated with either vehicle or Cardamonin starting from the same day or 16 weeks after the first AOM injection. Cardamonin treatment inhibited the tumor incidence, tumor multiplicity, Ki-67 and β-catenin positive cells. The activation of NF-kB signaling was also abrogated after cardamonin treatment. To elucidate the mechanism of action a global microRNA profiling of colon samples was performed. Computational analysis revealed that there is a differential expression of miRNAs between these groups. Subsequently, we extend our findings to human colorectal cancer and found that cardamonin inhibited the growth, induces cell cycle arrest and apoptosis in human colorectal cancer cell lines. Taken together, our study provides a better understanding of chemopreventive potential of cardamonin in colorectal cancer.
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Jacob H, Stanisavljevic L, Storli KE, Hestetun KE, Dahl O, Myklebust MP. Identification of a sixteen-microRNA signature as prognostic biomarker for stage II and III colon cancer. Oncotarget 2017; 8:87837-87847. [PMID: 29152124 PMCID: PMC5675676 DOI: 10.18632/oncotarget.21237] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 08/25/2017] [Indexed: 01/15/2023] Open
Abstract
Despite advances in colon cancer research and novel therapies, high risk of recurrence remains a major challenge. This study reports miRNA expression profiling as a biomarker for the prognosis of TNM stage II and III colon cancer. Fresh frozen biopsies from the study cohort (N=111) were analyzed for miRNA by RT-qPCR and LASSO regression analysis was used to build a classifier of miRNAs. The prognostic accuracy was tested and the classifier was validated in an independent colon cohort (TCGA-COAD, N=209). The LASSO regression analysis identified a 16-miRNA signature including miR-143-5p, miR-27a-3p, miR-31-5p, miR-181a-5p, miR-30b-5p, miR-30d-5p, miR-146a-5p, miR-23a-3p, miR-150-5p, miR-210-3p, miR-25-3p, miR-196a-5p, miR-148a-3p, miR-222-3p, miR-30c-5p and miR-223-3p. A low 16-miRNA signature was associated with better 5-year disease-free survival (DFS) in the study cohort than a high signature (93 % versus 58 %; p< 0.001). The signature was an independent prognostic factor for better 5-year DFS in multivariate analyses (HR 21.4; 95% CI: 4.21-108.7; p< 0.001). The results in the validation cohort were consistent with the study cohort in univariate (77 % versus 65 %; p= 0.045) and multivariate analyses (HR 2.0; 95% CI: 1.04-3.89; p=0.039). We identified a 16-miRNA signature as a reliable prognostic biomarker for classification of colon cancer stage II and III patients into groups with low and high risk for recurrence.
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Affiliation(s)
- Havjin Jacob
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Luka Stanisavljevic
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | | | - Kjersti E Hestetun
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway
| | - Olav Dahl
- Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.,Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
| | - Mette P Myklebust
- Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway
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Jeppsson S, Srinivasan S, Chandrasekharan B. Neuropeptide Y (NPY) promotes inflammation-induced tumorigenesis by enhancing epithelial cell proliferation. Am J Physiol Gastrointest Liver Physiol 2017; 312:G103-G111. [PMID: 27856419 PMCID: PMC5338605 DOI: 10.1152/ajpgi.00410.2015] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 11/10/2016] [Accepted: 11/10/2016] [Indexed: 02/07/2023]
Abstract
UNLABELLED We have demonstrated that neuropeptide Y (NPY), abundantly produced by enteric neurons, is an important regulator of intestinal inflammation. However, the role of NPY in the progression of chronic inflammation to tumorigenesis is unknown. We investigated whether NPY could modulate epithelial cell proliferation and apoptosis, and thus regulate tumorigenesis. Repeated cycles of dextran sodium sulfate (DSS) were used to model inflammation-induced tumorigenesis in wild-type (WT) and NPY knockout (NPY-/-) mice. Intestinal epithelial cell lines (T84) were used to assess the effects of NPY (0.1 µM) on epithelial proliferation and apoptosis in vitro. DSS-WT mice exhibited enhanced intestinal inflammation, polyp size, and polyp number (7.5 ± 0.8) compared with DSS-NPY-/- mice (4 ± 0.5, P < 0.01). Accordingly, DSS-WT mice also showed increased colonic epithelial proliferation (PCNA, Ki67) and reduced apoptosis (TUNEL) compared with DSS-NPY-/- mice. The apoptosis regulating microRNA, miR-375, was significantly downregulated in the colon of DSS-WT (2-fold, P < 0.01) compared with DSS-NPY-/--mice. In vitro studies indicated that NPY promotes cell proliferation (increase in PCNA and β-catenin, P < 0.05) via phosphatidyl-inositol-3-kinase (PI3-K)-β-catenin signaling, suppressed miR-375 expression, and reduced apoptosis (increase in phospho-Bad). NPY-treated cells also displayed increased c-Myc and cyclin D1, and reduction in p21 (P < 0.05). Addition of miR-375 inhibitor to cells already treated with NPY did not further enhance the effects induced by NPY alone. Our findings demonstrate a novel regulation of inflammation-induced tumorigenesis by NPY-epithelial cross talk as mediated by activation of PI3-K signaling and downregulation of miR-375. NEW & NOTEWORTHY Our work exemplifies a novel role of neuropeptide Y (NPY) in regulating inflammation-induced tumorigenesis via two modalities: first by enhanced proliferation (PI3-K/pAkt), and second by downregulation of microRNA-375 (miR-375)-dependent apoptosis in intestinal epithelial cells. Our data establish the existence of a microRNA-mediated cross talk between enteric neurons producing NPY and intestinal epithelial cells, and the potential of neuropeptide-regulated miRNAs as potential therapeutic molecules for the management of inflammation-associated tumors in the gut.
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Affiliation(s)
- Sabrina Jeppsson
- 1Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia;
| | - Shanthi Srinivasan
- 1Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; ,2Veterans Affairs Medical Center, Decatur, Atlanta, Georgia; and
| | - Bindu Chandrasekharan
- Division of Digestive Diseases, Department of Medicine, Emory University, Atlanta, Georgia; .,Georgia Institute of Technology, Atlanta, Georgia
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Cui ML, Zhang MX, Zhang C, Wang JJ. Role of cancer-related inflammation in colon cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:4343-4353. [DOI: 10.11569/wcjd.v24.i32.4343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic inflammation is one of the important mechanisms for the development of colon cancer, and the role of cancer-related inflammation (CRI) in tumor development is a hot research topic in recent years. Therefore, it is very important to clarify the effect and regulation of CRI in colon cancer. Accumulating evidence indicates that transcription factors, cytokines, chemokines, cyclooxygenase-2 and microRNAs play key roles in CRI. This review focuses on the research progress about these molecules in colon cancer.
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Shi C, Yang Y, Xia Y, Okugawa Y, Yang J, Liang Y, Chen H, Zhang P, Wang F, Han H, Wu W, Gao R, Gasche C, Qin H, Ma Y, Goel A. Novel evidence for an oncogenic role of microRNA-21 in colitis-associated colorectal cancer. Gut 2016; 65:1470-81. [PMID: 25994220 DOI: 10.1136/gutjnl-2014-308455] [Citation(s) in RCA: 112] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 04/24/2015] [Indexed: 12/12/2022]
Abstract
OBJECTIVE miR-21 was found to be overexpressed in the colon tissues and serum of patients with UC and colorectal cancer (CRC); however, the exact roles of miR-21 in colitis-associated CRC remain unclear. The aim of our study was to investigate the biological mechanisms of miR-21 in colitis-associated colon cancer (CAC). DESIGN miR-21 expression was examined in the tumours of 62 patients with CRC from China and 37 colitis-associated neoplastic tissues from Japan and Austria. The biological functions of miR-21 were studied using a series of in vitro, in vivo and clinical approaches. RESULTS miR-21 levels were markedly upregulated in the tumours of 62 patients with CRC, 22 patients with CAC, and in a mouse model of CAC. Following azoxymethane and dextran sulfate sodium intervention, miR-21-knockout mice showed reduced expression of proinflammatory and procarcinogenic cytokines (interleukin (IL) 6, IL-23, IL-17A and IL-21) and a decrease in the size and number of tumours compared with the control mouse group. The absence of miR-21 resulted in the reduced expression of Ki67 and the attenuated proliferation of tumour cells with a simultaneous increase in E-cadherin and decrease in β-catenin and SOX9 in the tumours of CAC mice. Furthermore, the absence of miR-21 increased the expression of its target gene PDCD4 and subsequently modulated nuclear factor (NF)-κB activation. Meanwhile, miR-21 loss reduced STAT3 and Bcl-2 activation, causing an increase in the apoptosis of tumour cells in CAC mice. CONCLUSIONS These observations provide novel evidence for miR-21 blockade to be a key strategy in reducing CAC.
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Affiliation(s)
- Chenzhang Shi
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yongzhi Yang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yang Xia
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
| | - Jun Yang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yong Liang
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hongqi Chen
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Peng Zhang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Feng Wang
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Huazhong Han
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wen Wu
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Renyuan Gao
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Christoph Gasche
- Division of Gastroenterology and Hepatology, Department of Medicine 4, Medical University Vienna, Vienna, Austria
| | - Huanlong Qin
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Yanlei Ma
- Department of GI Surgery, Shanghai Tenth People's Hospital Affiliated to Tongji University, Shanghai, China
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Baylor Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA
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Gareri C, De Rosa S, Indolfi C. MicroRNAs for Restenosis and Thrombosis After Vascular Injury. Circ Res 2016; 118:1170-84. [PMID: 27034278 DOI: 10.1161/circresaha.115.308237] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/01/2016] [Indexed: 12/21/2022]
Abstract
Percutaneous revascularization revolutionized the therapy of patients with coronary artery disease. Despite continuous technical advances that substantially improved patients' outcome after percutaneous revascularization, some issues are still open. In particular, restenosis still represents a challenge, even though it was dramatically reduced with the advent of drug-eluting stents. At the same time, drug-eluting stent thrombosis emerged as a major concern because of incomplete or delayed re-endothelialization after vascular injury. The discovery of microRNAs revealed a previously unknown layer of regulation for several biological processes, increasing our knowledge on the biological mechanisms underlying restenosis and stent thrombosis, revealing novel promising targets for more efficient and selective therapies. The present review summarizes recent experimental and clinical evidence on the role of microRNAs after arterial injury, focusing on practical aspects of their potential therapeutic application for selective inhibition of smooth muscle cell proliferation, enhancement of endothelial regeneration, and inhibition of platelet activation after coronary interventions. Application of circulating microRNAs as potential biomarkers is also discussed.
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Affiliation(s)
- Clarice Gareri
- From the Department of Medicine, Duke University, Durham, NC (C.G.); Division of Cardiology, Department of Medical and Surgical Science, "Magna Graecia" University, Catanzaro, Italy (S.D.R., C.I.); and URT-CNR, Department of Medicine, URT of Consiglio Nazionale delle Ricerche, Catanzaro, Italy (C.I.)
| | - Salvatore De Rosa
- From the Department of Medicine, Duke University, Durham, NC (C.G.); Division of Cardiology, Department of Medical and Surgical Science, "Magna Graecia" University, Catanzaro, Italy (S.D.R., C.I.); and URT-CNR, Department of Medicine, URT of Consiglio Nazionale delle Ricerche, Catanzaro, Italy (C.I.)
| | - Ciro Indolfi
- From the Department of Medicine, Duke University, Durham, NC (C.G.); Division of Cardiology, Department of Medical and Surgical Science, "Magna Graecia" University, Catanzaro, Italy (S.D.R., C.I.); and URT-CNR, Department of Medicine, URT of Consiglio Nazionale delle Ricerche, Catanzaro, Italy (C.I.).
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Yang Q, Xu H, Yang J, Zhou Y, Zhao D, Liu F. MicroRNA-223 affects IL-6 secretion in mast cells via the IGF1R/PI3K signaling pathway. Int J Mol Med 2016; 38:507-12. [PMID: 27354148 DOI: 10.3892/ijmm.2016.2649] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 05/18/2016] [Indexed: 11/05/2022] Open
Abstract
In this study, we aimed to assess the effects of microRNA-223 (miR-223) on interleukin-6 (IL-6) secretion in mast cells and determine the underlying molecular mechanisms. Mast cells (P815) were transfected with miR-223 lentiviral vector and miR-223 inhibitor. miR-223 expression was then evaluated using reverse transcription-quantitative PCR (RT-qPCR). IL-6 levels in the supernatant were analyzed using enzyme-linked immunosorbent assay. The signaling pathways in mast cells with downregulated miR-223 were initially evaluated by gene chip. Downregulation of miR-223 and its target gene was tested using a luciferase reporter assay. The expression of phosphate-AKT (p-AKT) and its target protein insulin-like growth factor-1 receptor (IGF1R) was assessed by western blot analysis. Phosphatidylinositol 3-kinase (PI3K)-inhibitor (LY294002) and insulin-like growth factor-1 (IGF1) were used to determine the effect of miR-223 on IL-6 secretion in mast cells. The results showed that microRNA-223 reduced IL-6 concentration in the mast cells. The gene chip results predicted an induction of the PI3K-AKT signaling pathway in the mast cells. Luciferase reporter assay confirmed IGF1R gene to be a target of miR-223. The p-AKT and IGF1R levels increased following miR-223 downregulation in mast cells. In addition, the specific PI3K‑inhibitor LY294002 decreased IL-6 secretion. Incubation with IGF1 resulted in the induction of IL-6 secretion in miR-223‑expressing mast cells. In conclusion, it was shown that miR-223 reduces IL-6 secretion in mast cells by inhibiting the IGF1R/PI3K signaling pathway.
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Affiliation(s)
- Qianyuan Yang
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Hong Xu
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Jin Yang
- Department of Pediatrics, Jiangsu Huai'an Maternity and Children's Hospital, Huai'an, Jiangsu 223002, P.R. China
| | - Yao Zhou
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Deyu Zhao
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
| | - Feng Liu
- Department of Respiratory Medicine, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, Jiangsu 210008, P.R. China
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Sonis ST, Amaral Mendes R. Could the PI3K canonical pathway be a common link between chronic inflammatory conditions and oral carcinogenesis? J Oral Pathol Med 2016; 45:469-74. [PMID: 26991523 DOI: 10.1111/jop.12436] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2016] [Indexed: 12/15/2022]
Abstract
The association between chronic inflammatory disorders and oral carcinogenesis has been both a source of interest and contention. Based upon its central importance in oral carcinogenesis, the finding that the PI3k/Akt/mTOR pathway is activated in oral lichen planus, chronic graft-versus-host disease, and chronic oral candidiasis suggests that it may provide a link between benign and malignant oral conditions. Here, we discuss a possible mechanistic rationale that addresses the activation of this important signaling pathway and its downstream events, while correlating it with the carcinogenic potential of chronic oral disorders.
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Affiliation(s)
- Stephen T Sonis
- Brigham and Women's Hospital and the Dana-Farber Cancer Institute and Biomodels LLC, Boston, MA, USA
| | - Rui Amaral Mendes
- Adjunct Professor of Oral and Maxillofacial Medicine, Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, School of Dental Medicine, Case Western Reserve University, Cleveland, OH, USA
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Law IKM, Jensen D, Bunnett NW, Pothoulakis C. Neurotensin-induced miR-133α expression regulates neurotensin receptor 1 recycling through its downstream target aftiphilin. Sci Rep 2016; 6:22195. [PMID: 26902265 PMCID: PMC4763298 DOI: 10.1038/srep22195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Accepted: 02/09/2016] [Indexed: 01/05/2023] Open
Abstract
Neurotensin (NT) triggers signaling in human colonic epithelial cells by activating the G protein-coupled receptor, the neurotensin receptor 1 (NTR1). Activated NTR1 traffics from the plasma membrane to early endosomes, and then recycles. Although sustained NT/NTR1 signaling requires efficient NTR1 recycling, little is known about the regulation of NTR1 recycling. We recently showed that NT/NTR1 signaling increases expression of miR-133α. Herein, we studied the mechanism of NT-regulated miR-133α expression and examined the role of miR-133α in intracellular NTR1 trafficking in human NCM460 colonocytes. We found that NT-induced miR-133α upregulation involves the negative transcription regulator, zinc finger E-box binding homeobox 1. Silencing of miR-133α or overexpression of aftiphilin (AFTPH), a binding target of miR-133α, attenuated NTR1 trafficking to plasma membrane in human colonocytes, without affecting NTR1 internalization. We localized AFTPH to early endosomes and the trans-Golgi network (TGN) in unstimulated human colonic epithelial cells. AFTPH overexpression reduced NTR1 localization in early endosomes and increased expression of proteins related to endosomes and the TGN trafficking pathway. AFTPH overexpression and de-acidification of intracellular vesicles increased NTR1 expression. Our results suggest a novel mechanism of GPCR trafficking in human colonic epithelial cells by which a microRNA, miR-133α regulates NTR1 trafficking through its downstream target AFTPH.
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Affiliation(s)
- Ivy Ka Man Law
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, California, USA
| | - Dane Jensen
- Monash Institute of Pharmaceutical Sciences, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Parkville, Monash University, Australia
- Department of Anesthesia and Peri-operative Medicine, Monash University, Australia
| | - Nigel W. Bunnett
- Monash Institute of Pharmaceutical Sciences, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Parkville, Monash University, Australia
- Department of Anesthesia and Peri-operative Medicine, Monash University, Australia
- Department of Pharmacology and Therapeutics, University of Melbourne, Australia
| | - Charalabos Pothoulakis
- Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, University of California at Los Angeles, California, USA
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MicroRNAs and Inflammation in Colorectal Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 937:53-69. [PMID: 27573894 DOI: 10.1007/978-3-319-42059-2_3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancers (CRC) are known to be related to inflammatory conditions, and inflammatory bowel diseases increase the relative risk for developing CRC. The use of anti-inflammatory drugs prevents the development of colorectal cancer.Several molecular mediators are connecting the pathways that are involved in inflammatory conditions and in carcinogenesis. By the way these pathways are tightly interwoven, with the consequence that a deregulation at the level of any of these molecular mediators can affect the others.MiRNAs are demonstrated to be deregulated in inflammatory bowel diseases and in colorectal cancer. Moreover, they target several molecular mediators that connect inflammation to cancer, and they are thus implicated in the route from inflammation to colorectal cancer.This chapter will focus on the miRNAs that are jointly deregulated in inflammatory bowel disease and in colorectal cancer. Their role on the regulation of the molecular mediators and pathways that link inflammation to cancer will be described.
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