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Jafarzadeh A, Zandvakili R, Jafarzadeh Z, Nemati M. Dysregulated expression of the suppressors of cytokine signaling (SOCS) contributes to the development of prostate cancer. Pathol Res Pract 2024; 262:155558. [PMID: 39213689 DOI: 10.1016/j.prp.2024.155558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 08/22/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024]
Abstract
Different types of cytokines, growth factors, or hormones present within the tumor microenvironment that can activate the JAK-STAT signaling pathway by binding to their specific cell surface receptors. The constitutive activation of the JAK-STAT pathway can promote uncontrolled cell proliferation and prevent apoptosis contributing to tumor development. Activation of the JAK-STAT pathway is controlled by several regulatory molecules, particularly the suppressor of cytokine signaling (SOCS) family consisting of eight members, which include SOCS1-SOCS7 and the cytokine-inducible SH2-containing (CIS) proteins. In prostate cancer cells, the irregular expression of the SOCS1-SOCS3, SOCS5-SOCS7 as well as CIS can similarly and differentially result in the initiation of various cellular signaling pathways (in particular JAK-STAT3, MAPK, ERK) that promote cell proliferation, migration, invasion and viability; cell cycle progression; epithelial-mesenchymal transition; angiogenesis; resistance to therapy; immune evasion; and chronic inflammation within the tumor microenvironment which lead to tumor progression, metastasis and poor prognosis. Epigenetic modifications, mainly due to DNA methylation, microRNAs, pro-inflammatory cytokines, growth factors and androgens can influence the expression of the SOCS molecules in prostate cancer cells. Using strategies to modulate, restore or enhance the expression of SOCS proteins, may help overcome treatment resistance and improve the efficacy of existing therapies. In this review, we provide a comprehensive explanation regarding SOCS dysregulation in prostate cancer to provide insights into the mechanisms underlying the dysregulation of SOCS proteins. This knowledge may pave the way for the development of novel therapeutic strategies to manage prostate cancer by restoring and modulating the expression of SOCS molecules.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran.
| | - Raziyeh Zandvakili
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Jafarzadeh
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran; Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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Jafarzadeh A, Jafarzadeh Z, Nemati M, Yoshimura A. The Interplay Between Helicobacter pylori and Suppressors of Cytokine Signaling (SOCS) Molecules in the Development of Gastric Cancer and Induction of Immune Response. Helicobacter 2024; 29:e13105. [PMID: 38924222 DOI: 10.1111/hel.13105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 06/04/2024] [Accepted: 06/06/2024] [Indexed: 06/28/2024]
Abstract
Helicobacter pylori (H. pylori) colonizes the stomach and leads to the secretion of a vast range of cytokines by infiltrated leukocytes directing immune/inflammatory response against the bacterium. To regulate immune/inflammatory responses, suppressors of cytokine signaling (SOCS) proteins bind to multiple signaling components located downstream of cytokine receptors, such as Janus kinase (JAK), signal transducers and activators of transcription (STAT). Dysfunctional SOCS proteins in immune cells may facilitate the immune evasion of H. pylori, allowing the bacteria to induce chronic inflammation. Dysregulation of SOCS expression and function can contribute to the sustained H. pylori-mediated gastric inflammation which can lead to gastric cancer (GC) development. Among SOCS molecules, dysregulated expression of SOCS1, SOCS2, SOCS3, and SOCS6 were indicated in H. pylori-infected individuals as well as in GC tissues and cells. H. pylori-induced SOCS1, SOCS2, SOCS3, and SOCS6 dysregulation can contribute to the GC development. The expression of SOCS molecules can be influenced by various factors, such as epigenetic DNA methylation, noncoding RNAs, and gene polymorphisms. Modulation of the expression of SOCS molecules in gastric epithelial cells and immune cells can be considered to control gastric carcinogenesis as well as regulate antitumor immune responses, respectively. This review aimed to explain the interplay between H. pylori and SOCS molecules in GC development and immune response induction as well as to provide insights regarding potential therapeutic strategies modulating SOCS molecules.
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Affiliation(s)
- Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Applied Cellular and Molecular Research Center, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Jafarzadeh
- Student Research Committee, Faculty of Pharmacy, Kerman University of Medical Sciences, Kerman, Iran
| | - Maryam Nemati
- Department of Hematology and Laboratory Sciences, School of Para-Medicine, Kerman University of Medical Sciences, Kerman, Iran
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Akihiko Yoshimura
- Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan
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Chen J, Wang L, Ma D, Zhang H, Fan J, Gao H, Xia X, Wu W, Shi Y. miR-19a may function as a biomarker of oral squamous cell carcinoma (OSCC) by regulating the signaling pathway of miR-19a/GRK6/GPCRs/PKC in a Chinese population. J Oral Pathol Med 2023; 52:971-979. [PMID: 37706561 DOI: 10.1111/jop.13478] [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: 06/10/2023] [Revised: 08/16/2023] [Accepted: 08/25/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND In this study, we aimed to investigate the potential of miR-19a as a biomarker of OSCC and its underlying molecular mechanisms. METHODS We collected serum and saliva samples from 66 OSCC patients and 66 healthy control subjects. Real-time PCR analysis, bioinformatic analysis and luciferase assays were performed to establish a potential signaling pathway of miR-19a/GRK6/GPCRs/PKC. Flowcytometry and Transwell assays were performed to observe the changes in cell apoptosis, metastasis and invasion. RESULTS We found that miR-19a, GPR39 mRNA and PKC mRNA were upregulated while GRK6 mRNA was downregulated in the serum and saliva samples collected from OSCC patients. Moreover, in silico analysis confirmed a potential binding site of miR-19a on the 3'UTR of GRK6 mRNA, and the subsequent luciferase assays confirmed the molecular binding between GRK6 and miR-19a. We further identified that the over-expression of miR-19a could regulate the signaling between GRK6, GPR39 and PKC via the signaling pathway of miR-19a/GRK6/GPR39/PKC, which accordingly resulted in suppressed cell apoptosis and promoted cell migration and invasion. CONCLUSION Collectively, the findings of our study propose that miR-19a is a crucial mediator in the advancement of OSCC, offering a potential avenue for the development of innovative therapeutic interventions aimed at regulating GRK6 and its downstream signaling pathways.
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Affiliation(s)
- Jijun Chen
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Liang Wang
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Danhua Ma
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - He Zhang
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Jiayan Fan
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Hongyan Gao
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Xinyu Xia
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Wei Wu
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
| | - Yuyuan Shi
- Department of Stomatology, Ningbo No. 2 Hospital, Ningbo, Zhejiang, China
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Yan P, Cheng M, Wang L, Zhao W. A ferroptosis-related gene in Helicobacter pylori infection, SOCS1, serves as a potential prognostic biomarker and corresponds with tumor immune infiltration in stomach adenocarcinoma: In silico approach. Int Immunopharmacol 2023; 119:110263. [PMID: 37156031 DOI: 10.1016/j.intimp.2023.110263] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/10/2023] [Accepted: 04/28/2023] [Indexed: 05/10/2023]
Abstract
OBJECTIVE Helicobacter pylori (H. pylori) is a major risk factor for the stomach adenocarcinoma (STAD). This study aimed to investigate the potential role of a H. pylori infection-related gene, SOCS1, in STAD. MATERIALS AND METHODS Online available databases were analyzed to determine the expression, correlations with clinicopathologic parameters, patients' survival, and immunological characteristics of SOCS1 in TCGA-STAD or GEO datasets. Univariate and multivariate Cox regression analyses were used to determine independent risk factors, which were further integrated to establish a nomogram. A comparison of drug sensitivity was conducted for the chemotherapy responses between individuals with low- and high-SOCS1. Prediction of tumor response to checkpoint inhibitors was based on the tumor immunodeficiency and exclusion (TIDE) score. RESULTS SOCS1 expression was significantly increased in both H. pylori-infected and STAD patients. Higher SOCS1 expression indicated an undesirable prognosis in STAD patients. SOCS1 upregulation was related to enhanced immune cell infiltrations and the upregulation of immune checkpoints in STAD patients. N stage, age and SOCS1 were identified as independent risk factors for higher mortality of STAD patients and confirmed using the nomogram. Drug sensitivity analyses demonstrated that high expression of SOCS1 in STAD patients could improve the sensitivity to chemotherapy. TIDE score showed that STAD patients with high SOCS1 expression would have superior response to immunotherapy. CONCLUSIONS SOCS1 may act as a potential biomarker for uncovering the underlying mechanisms of gastric cancer. Increasing the activity of immunotherapy through ferroptosis-immunomodulation may be a viable strategy in STAD therapy.
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Affiliation(s)
- Ping Yan
- Department of Gastroenterology, First Affiliated Hospital of Dali University, Dali, China
| | - Mingjing Cheng
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, China
| | - Li Wang
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, China
| | - Weidong Zhao
- Department of Clinical Laboratory, School of Clinical Medicine, Dali University, Dali, China; Department of Clinical Laboratory, Second Infectious Disease Hospital of Yunnan Province, Dali, China; Immunology Discipline Team, School of Basic Medicine, Dali University, Dali, China.
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Keewan E, Matlawska-Wasowska K. The Emerging Role of Suppressors of Cytokine Signaling (SOCS) in the Development and Progression of Leukemia. Cancers (Basel) 2021; 13:4000. [PMID: 34439155 PMCID: PMC8393695 DOI: 10.3390/cancers13164000] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/12/2022] Open
Abstract
Cytokines are pleiotropic signaling molecules that execute an essential role in cell-to-cell communication through binding to cell surface receptors. Receptor binding activates intracellular signaling cascades in the target cell that bring about a wide range of cellular responses, including induction of cell proliferation, migration, differentiation, and apoptosis. The Janus kinase and transducers and activators of transcription (JAK/STAT) signaling pathways are activated upon cytokines and growth factors binding with their corresponding receptors. The SOCS family of proteins has emerged as a key regulator of cytokine signaling, and SOCS insufficiency leads to constitutive activation of JAK/STAT signaling and oncogenic transformation. Dysregulation of SOCS expression is linked to various solid tumors with invasive properties. However, the roles of SOCS in hematological malignancies, such as leukemia, are less clear. In this review, we discuss the recent advances pertaining to SOCS dysregulation in leukemia development and progression. We also highlight the roles of specific SOCS in immune cells within the tumor microenvironment and their possible involvement in anti-tumor immunity. Finally, we discuss the epigenetic, genetic, and post-transcriptional modifications of SOCS genes during tumorigenesis, with an emphasis on leukemia.
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Affiliation(s)
- Esra’a Keewan
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
| | - Ksenia Matlawska-Wasowska
- Department of Pediatrics, Division of Hematology and Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA;
- Comprehensive Cancer Center, University of New Mexico, Albuquerque, NM 87131, USA
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Jin X, Su H, Xu L, Wang Y, Su R, Zhang Z, Guan G, Li Z. Different co-culture models reveal the pivotal role of TBBPA-promoted M2 macrophage polarization in the deterioration of endometrial cancer. JOURNAL OF HAZARDOUS MATERIALS 2021; 413:125337. [PMID: 33609860 DOI: 10.1016/j.jhazmat.2021.125337] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/18/2021] [Accepted: 02/03/2021] [Indexed: 06/12/2023]
Abstract
Tetrabromobisphenol A (TBBPA), an emerging organic pollutant widely detected in human samples, has a positive correlation with the development of endometrial cancer (EC), but its underlying mechanisms have not yet been fully elucidated. Tumor-associated macrophages (TAM), one of the most vital components in tumor microenvironment (TME), play regulatory roles in the progression of EC. Consequently, this study mainly focuses on the macrophage polarization in TME to unveil the influence of TBBPA on the progression of EC and involved mechanisms. Primarily, low doses of TBBPA treatment up-regulated M2-like phenotype biomarkers in macrophage. The data from in vitro co-culture models suggested TBBPA-driven M2 macrophage polarization was responsible for the EC deterioration. Results from in vivo study further confirmed the malignant proliferation of EC promoted by TBBPA. Mechanistically, TBBPA-mediated miR-19a bound to the 3'-UTR regions of SOCS1, resulting in down-regulation of SOCS1 followed by the phosphorylation of JAK and STAT6. The present study not only revealed for the first time the molecular mechanism of TBBPA-induced EC's deterioration based on macrophage polarization, but also established co-culture models, thus providing a further evaluation method for the exploration of environmental pollutants-induced tumor effects from the role of TME.
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Affiliation(s)
- Xiaoting Jin
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China; School of Public Health, Qingdao University, Qingdao, China
| | - Huilan Su
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China; Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China
| | - Liting Xu
- School of Public Health, Qingdao University, Qingdao, China
| | - Yu Wang
- School of Public Health, Qingdao University, Qingdao, China
| | - Ruijun Su
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China; Department of Biology, Taiyuan Normal University, Taiyuan, China
| | - Ze Zhang
- School of Public Health, Qingdao University, Qingdao, China
| | - Ge Guan
- School of Public Health, Qingdao University, Qingdao, China
| | - Zhuoyu Li
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi University, Taiyuan, China; Institutes of Biomedical Sciences, Shanxi University, Taiyuan, China.
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Role of miRNA-19a in Cancer Diagnosis and Poor Prognosis. Int J Mol Sci 2021; 22:ijms22094697. [PMID: 33946718 PMCID: PMC8125123 DOI: 10.3390/ijms22094697] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 04/25/2021] [Accepted: 04/27/2021] [Indexed: 12/30/2022] Open
Abstract
Cancer is a multifactorial disease that affects millions of people every year and is one of the most common causes of death in the world. The high mortality rate is very often linked to late diagnosis; in fact, nowadays there are a lack of efficient and specific markers for the early diagnosis and prognosis of cancer. In recent years, the discovery of new diagnostic markers, including microRNAs (miRNAs), has been an important turning point for cancer research. miRNAs are small, endogenous, non-coding RNAs that regulate gene expression. Compelling evidence has showed that many miRNAs are aberrantly expressed in human carcinomas and can act with either tumor-promoting or tumor-suppressing functions. miR-19a is one of the most investigated miRNAs, whose dysregulated expression is involved in different types of tumors and has been potentially associated with the prognosis of cancer patients. The aim of this review is to investigate the role of miR-19a in cancer, highlighting its involvement in cell proliferation, cell growth, cell death, tissue invasion and migration, as well as in angiogenesis. On these bases, miR-19a could prove to be truly useful as a potential diagnostic, prognostic, and therapeutic marker.
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Ma RR, Zhang H, Chen HF, Zhang GH, Tian YR, Gao P. MiR-19a/miR-96-mediated low expression of KIF26A suppresses metastasis by regulating FAK pathway in gastric cancer. Oncogene 2021; 40:2524-2538. [PMID: 33674746 DOI: 10.1038/s41388-020-01610-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Revised: 11/27/2020] [Accepted: 12/09/2020] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is one of the most common malignant neoplasms. Invasion and metastasis are the main causes of GC-related deaths. Recently, kinesins were discovered to be involved in tumor development. The aim of this study was to elucidate the roles of kinesin superfamily protein 26A (KIF26A) in GC and its underlying molecular mechanism in regulating tumor invasion and metastasis. Using real-time quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), we showed that KIF26A expression was lower in GC tissues without lymph node metastasis (LNM) than in nontumorous gastric mucosa, and even lower in GC tissues with LNM than in GC tissues without LNM. Functional experiments showed that KIF26A inhibited migration and invasion of GC cells. We further identified focal-adhesion kinase (FAK), phosphatidylinositol 3-kinase regulatory subunit alpha (PI3KR1), VAV3, Rac1 and p21-activated kinase 2, and β-PAK (PAK3) as downstream effectors of KIF26A in the focal-adhesion pathway, and we found that KIF26A could regulate FAK mRNA expression through inhibiting c-MYC by MAPK pathway. c-MYC could bind to the promoter of FAK and activate FAK transcription. Moreover, we found that KIF26A-mediated inactivation of the focal-adhesion pathway could reduce the occurrence of the epithelial-to-mesenchymal transition (EMT) by increasing expression of E-cadherin and reducing that of Snail. Luciferase assays and Western blotting revealed that miR-19a and miR-96 negatively regulate KIF26A. Finally, we found that decreased expression of KIF26A has been positively correlated with histological differentiation, Lauren classification, LNM, distal metastasis, and clinical stage, as well as poor survival in patients with GC. These data indicate that KIF26A could inhibit GC migration and invasion by regulating the focal-adhesion pathway and repressing the occurrence of EMT.
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Affiliation(s)
- Ran-Ran Ma
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hui Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China
| | - Hong-Fang Chen
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.,Department of Pathology, Yidu Central Hospital of Weifang, Weifang, PR China
| | - Guo-Hao Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Ya-Ru Tian
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Peng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, PR China. .,Department of Pathology, Qilu Hospital, Shandong University, Jinan, PR China.
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Weidle UH, Birzele F, Nopora A. microRNAs Promoting Growth of Gastric Cancer Xenografts and Correlation to Clinical Prognosis. Cancer Genomics Proteomics 2021; 18:1-15. [PMID: 33419892 DOI: 10.21873/cgp.20237] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 02/06/2023] Open
Abstract
The annual death toll for gastric cancer is in the range of 700,000 worldwide. Even in patients with early-stage gastric cancer recurrence within five years has been observed after surgical resection and following chemotherapy with therapy-resistant features. Therefore, the identification of new targets and treatment modalities for gastric cancer is of paramount importance. In this review we focus on the role of microRNAs with documented efficacy in preclinical xenograft models with respect to growth of human gastric cancer cells. We have identified 31 miRs (-10b, -19a, -19b, -20a, -23a/b, -25, -27a-3p, -92a, -93, -100, -106a, -130a, -135a, -135b-5p, -151-5p, -187, -199-3p, -215, -221-3p, -224, -340a, -382, -421, -425, -487a, -493, -532-3p, -575, -589, -664a-3p) covering 26 different targets which promote growth of gastric cancer cells in vitro and in vivo as xenografts. Five miRs (miRs -10b, 151-5p, -187, 532-3p and -589) additionally have an impact on metastasis. Thirteen of the identified miRs (-19b, -20a/b, -25, -92a, -106a, -135a, -187, -221-3p, -340a, -421, -493, -575 and -589) have clinical impact on worse prognosis in patients.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany;
| | - Fabian Birzele
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany;
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10
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Yi X, Liu C. Downregulation of microRNA-605 indicates poor prognosis and promotes the progression of osteosarcoma. Oncol Lett 2020; 20:370. [PMID: 33154768 PMCID: PMC7608056 DOI: 10.3892/ol.2020.12233] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/16/2020] [Indexed: 12/26/2022] Open
Abstract
Osteosarcoma (OS) is a type of primary bone tumor, which is one of the leading causes of cancer-related death. MicroRNA (miR)-605 has been demonstrated to act as a prognostic biomarker and therapeutic target in various cancers, such as breast cancer and non-small cell lung cancer, but its function in OS remains unclear. The aim of the present study was to investigate the prognostic value of miR-605 in patients with OS by evaluating its expression levels and to explore the biological function of miR-605 in OS progression. For this purpose, tumor tissues and adjacent normal tissues were collected from OS patients, and the expression of miR-605 in the collected tissues and OS MG63, U2OS, HOS, and SAOS-2 cell lines was detected by quantitative real-time PCR. The prognostic value of miR-605 was evaluated by Kaplan-Meier survival curves and Cox regression analysis. The effects of miR-605 on OS cell proliferation, migration and invasion were analyzed by the CCK-8 and transwell assays, respectively. The results of the present study revealed that miR-605 was significantly downregulated in OS tissues compared with adjacent normal tissues, which was associated with the clinical stage and distant metastasis of patients. Additionally, the downregulation of miR-605 predicted the poor prognosis of patients with OS and served as an independent prognostic indicator. The downregulation of miR-605 enhanced cell proliferation, migration, and invasion of OS cells, which suggested that miR-605 may be involved in the progression of OS. The findings of the present study provide a new therapeutic target for the treatment of patients with OS.
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Affiliation(s)
- Xiuling Yi
- Department of Spinal Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
| | - Chunlei Liu
- Department of Spinal Surgery, Weifang People's Hospital, Weifang, Shandong 261041, P.R. China
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11
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Lv Q, Xia Q, Li J, Wang Z. Allicin suppresses growth and metastasis of gastric carcinoma: the key role of microRNA-383-5p-mediated inhibition of ERBB4 signaling. Biosci Biotechnol Biochem 2020; 84:1997-2004. [PMID: 32597323 DOI: 10.1080/09168451.2020.1780903] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Allicin is a natural product suppressing the progression of gastric carcinoma (GC). In the current study, the mechanism underlying the anti-GC effect of allicin was explored by focusing on the role of miR-383-5p/ERBB4 signaling. Two GC cell lines were treated with allicin and the effects on viability, apoptosis, migration, invasion, and miR-383-5p/ERBB4 activity in the cells were assessed. The interaction between allicin and miR-383-5p was further explored by inhibiting the miR-383-5p level. Allicin suppressed cell viability and induced apoptosis in both GC cell lines. The compound also inhibited migration and invasion of GC cells, which was associated with the up-regulation miR-383-5p and down-regulation of ERBB4. The inhibition of miR-383-5p by specific inhibitor blocked the anti-GC effect of allicin. Our results demonstrated that allicin contributed to the suppressed growth and metastasis potentials in GC cell lines. The effect was accompanied by an increased level of miR-383-5p and subsequent inhibition of ERBB4.
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Affiliation(s)
- Qing Lv
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Qinghua Xia
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Jiang Li
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
| | - Zhiyong Wang
- Department of Gastrointestinal Surgery, Wuhan Union Hospital , Wuhan, China
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12
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Common and Unique microRNAs in Multiple Carcinomas Regulate Similar Network of Pathways to Mediate Cancer Progression. Sci Rep 2020; 10:2331. [PMID: 32047181 PMCID: PMC7012856 DOI: 10.1038/s41598-020-59142-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Accepted: 01/14/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer is a complex disease with a fatal outcome. Early detection of cancer, by monitoring appropriate molecular markers is very important for its therapeutic management. In this regard, the short non-coding RNA molecules, microRNAs (miRNAs) have shown great promise due to their availability in circulating fluids facilitating non-invasive detection of cancer. In this study, an in silico comparative analysis was performed to identify specific signature miRNAs dysregulated across multiple carcinomas and simultaneously identify unique miRNAs for each cancer type as well. The miRNA-seq data of cancer patient was obtained from GDC portal and their differential expressions along with the pathways regulated by both common and unique miRNAs were analyzed. Our studies show twelve miRNAs commonly dysregulated across seven different cancer types. Interestingly, four of those miRNAs (hsa-mir-210, hsa-mir-19a, hsa-mir-7 and hsa-mir-3662) are already reported as circulatory miRNAs (circRNAs); while, the miR-183 cluster along with hsa-mir-93 have been found to be incorporated in exosomes signifying the importance of the identified miRNAs for their use as prospective, non-invasive biomarkers. Further, the target mRNAs and pathways regulated by both common and unique miRNAs were analyzed, which interestingly had significant commonality. This suggests that miRNAs that are commonly de-regulated and specifically altered in multiple cancers might regulate similar pathways to promote cancer. Our data is of significance because we not only identify a set of common and unique miRNAs for multiple cancers but also highlight the pathways regulated by them, which might facilitate the development of future non-invasive biomarkers conducive for early detection of cancers.
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13
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Calabrese G, Dolcimascolo A, Caruso G, Forte S. miR-19a Is Involved In Progression And Malignancy Of Anaplastic Thyroid Cancer Cells. Onco Targets Ther 2019; 12:9571-9583. [PMID: 32009794 PMCID: PMC6859471 DOI: 10.2147/ott.s221733] [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: 07/03/2019] [Accepted: 08/13/2019] [Indexed: 12/15/2022] Open
Abstract
Background MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs acting as negative regulators of gene expression involved in a number of physiological processes. MiRNAs' expression is commonly dysregulated in many types of human tumor diseases and cancers, including thyroid cancers, and is often involved in tumor initiation and progression. miR-19a, a member of miR-17-92 cluster, has been demonstrated to promote cell growth in anaplastic thyroid cancer (ATC), the most advanced and aggressive thyroid cancer. Purpose In this work, we investigate the potential contribution of miR-19a in thyroid cancer cells poor prognosis and de-differentiation. Methods We directly modulated the expression of miR-19a in papillary (PTC) and anaplastic thyroid carcinoma cell lines through transfection of specific miR-19a mimic or inhibitor. Further, we performed gene expression analysis of specific genes to evaluate miR-19a association with cell cycle, differentiation, and poor prognosis. Results Our data indicate that miR-19a overexpression in PTC cells significantly promotes cell growth, decreases the expression of differentiation genes and activates poor prognosis genes. Its inhibition in ATC cells reduces cell proliferation and the expression of genes related to poor prognosis but does not affect differentiation. Conclusion Our findings reveal the existence of functional associations between miR-19a expression and thyroid cancer progression and malignancy suggesting miR-19a as a novel candidate therapeutic target for ATC.
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Affiliation(s)
- Giovanna Calabrese
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy
| | - Anna Dolcimascolo
- Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania 95123, Italy
| | - Giuseppe Caruso
- Department of Laboratories, Oasi Research Institute, IRCCs, Troina, EN 94018, Italy
| | - Stefano Forte
- Molecular Biology Unit, IOM Ricerca, Viagrande, CT 95029, Italy
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14
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Shayimu P, Wang JB, Liu L, Tuerdi R, Yu CG, Yusufu A. miR-922 regulates apoptosis, migration, and invasion by targeting SOCS1 in gastric cancer. Kaohsiung J Med Sci 2019; 36:178-185. [PMID: 31709719 DOI: 10.1002/kjm2.12155] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 10/17/2019] [Indexed: 01/28/2023] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death worldwide. Studies have shown that miR-922 facilitates the development of various diseases and tumors. However, the role of miR-922 in GC and related molecular mechanisms are still unrevealed. Current study indicated that miR-922 was overexpressed in GC tissues and cells. The survival rate of patients in high miR-922 expression group is significantly lower than that in low miR-922 expression group. In addition, overexpression of miR-922 observably restrained the apoptosis of SGC7901 cells and promoted SGC7901 cell proliferation, migration, and invasion. TargetScan predicted that suppressors of cytokine signaling 1 (SOCS1) was a potential target of miR-922. miR-922 upregulation profoundly inhibited the expression of SOCS1. Furthermore, the mRNA level of SOCS1 in GC tissues was significantly lower than that in adjacent tissues, indicating that miR-922 promoted the proliferation, invasion, and migration, and inhibited apoptosis of SGC7901 cells by downregulating the level of SOCS1. In conclusion, miR-922 may have potential for diagnosis of GC.
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Affiliation(s)
- Paerhati Shayimu
- Department of Gastrointestinal Surgery, The 3rd Affiliated Teaching Hospital of Xin Jiang Medical University (Affiliated Cancer Hospital), Urumqi, China
| | - Jing-Bin Wang
- Department of Spleen and Stomach Disease, Guangzhou University of Chinese Medicine-Shenzhen Hospital, Shenzhen, Guangdong Province, China
| | - Lin Liu
- Department of Gastrointestinal Surgery, The 3rd Affiliated Teaching Hospital of Xin Jiang Medical University (Affiliated Cancer Hospital), Urumqi, China
| | - Rousidan Tuerdi
- Graduate School, Xin Jiang Medical University, Urumqi, China
| | - Cun-Guo Yu
- Department of Chinese Medicine, Qinhuangdao Haigang Hospital, Qinhuangdao, Hebei Province, China
| | - Aikeremu Yusufu
- Department of Gastrointestinal Surgery, The 3rd Affiliated Teaching Hospital of Xin Jiang Medical University (Affiliated Cancer Hospital), Urumqi, China
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15
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Gong HL, Tao Y, Mao XZ, Song DY, You D, Ni JD. MicroRNA-29a suppresses the invasion and migration of osteosarcoma cells by regulating the SOCS1/NF-κB signalling pathway through negatively targeting DNMT3B. Int J Mol Med 2019; 44:1219-1232. [PMID: 31364725 PMCID: PMC6713425 DOI: 10.3892/ijmm.2019.4287] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 05/31/2019] [Indexed: 12/16/2022] Open
Abstract
The present study aimed to investigate the roles of the microRNA‑29a/DNA methyltransferase 3B/suppressor of cytokine signalling 1 (miR‑29a/DNMT3B/SOCS1) axis in the invasion and the migration of osteosarcoma (OS). The expression levels of miR‑29a, DNMT3B and SOCS1 were determined in tissue samples and OS cell lines by reverse transcription‑quantitative polymerase chain reaction (PCR). Apoptosis was measured using flow cytometry analysis. Transwell and wound healing assays were conducted to measure the invasion and migration abilities of OS cells, respectively. A dual‑luciferase reporter assay was also conducted to determine the interaction between DNMT3B and miR‑29a, while methylation‑specific PCR was used to detect the methylation of SOCS1. Western blotting was performed to determine the protein levels of DNMT3B and SOCS1, as well as the levels of proteins associated with epithelial‑mesenchymal transition (EMT), apoptosis and the nuclear factor (NF)‑κB signalling pathway. The results demonstrated that miR‑29a and SOCS1 were downregulated, and DNMT3B was upregulated in both OS tissues and cell lines. The expression of miR‑29a and SOCS1 was found to be associated with advanced clinical stage and distant metastasis. In addition, the dual‑luciferase reporter assay revealed that DNMT3B was a direct target of miR‑29a. Overexpression using miR‑29a mimics decreased DNMT3B expression and the methylation level of SOCS1, which resulted in the upregulation of SOCS1 in U2OS and MG‑63 cells, while miR‑29a inhibition led to the opposite results. Transfection with miR‑29a mimics also promoted the apoptosis, and inhibited the invasion, migration and EMT process of OS cells, while it markedly reduced the nuclear translocation of p65 and IκB‑α degradation. Treatment with 5‑aza‑2'‑deoxycytidine worked together with miR‑29a mimics to synergistically enhance the aforementioned effects. By contrast, the effects induced by miR‑29a were partly reversed upon co‑transfection with SOCS1 siRNA. In conclusion, miR‑29a promoted the apoptosis, and inhibited the invasion, migration and EMT process of OS cells via inhibition of the SOCS1/NF‑κB signalling pathway by directly targeting DNMT3B.
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Affiliation(s)
- Hao-Li Gong
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Ye Tao
- Department of Radiology, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Xin-Zhan Mao
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - De-Ye Song
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Di You
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jiang-Dong Ni
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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16
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Effect of plasma MicroRNA on antihypertensive response to beta blockers in the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) studies. Eur J Pharm Sci 2019; 131:93-98. [PMID: 30753892 DOI: 10.1016/j.ejps.2019.02.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 02/08/2019] [Accepted: 02/08/2019] [Indexed: 01/13/2023]
Abstract
β-blockers show variable efficacy as antihypertensives. Herein, we evaluated plasma miRNAs as biomarkers for defining antihypertensive response to β-blockers. Expression of 22 β-blocker pharmacodynamics-related miRNAs was assessed in baseline plasma samples from 30 responders and 30 non-responders to metoprolol from the PEAR-2 study (Discovery). Logistic regression was performed to identify miRNAs significantly associated with metoprolol response. Those miRNAs were profiled in baseline plasma samples from 25 responders and 25 non-responders to atenolol from the PEAR study (validation). In discovery, miR-101, miR-27a, miR-22, miR-19a, and let-7e were significantly associated with metoprolol response (P = 0.01, 0.017, 0.025, 0.025, and 0.04, respectively). In validation, miR-19a was significantly associated with atenolol response (P = 0.038). Meta-analysis between PEAR-2 and PEAR revealed significant association between miR-19a (P = 0.004), miR-101 (P = 0.006), and let-7e (P = 0.012) and β-blocker response. Hence, miR-19a, miR-101, and let-7e, which regulate β1-adrenergic receptor and other β-blocker pharmacodynamics-related genes, may be biomarkers for antihypertensive response to β-blockers.
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17
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Yu FQ, Wang Z, Wang XW, Wang SL, Li XD, Huang QS, Lin JH. MicroRNA-885-5p promotes osteosarcoma proliferation and migration by downregulation of cell division cycle protein 73 homolog expression. Oncol Lett 2018; 17:1565-1572. [PMID: 30675214 PMCID: PMC6341520 DOI: 10.3892/ol.2018.9802] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2017] [Accepted: 11/16/2018] [Indexed: 01/08/2023] Open
Abstract
Osteosarcoma (OS) is the most common primary malignant bone tumor. Numerous studies have strongly implicated the ectopic expression of microRNAs (miRNAs/miRs), including miR-885-5p, which is aberrantly expressed in several cancer types, in multiple cancer-related processes. However, the role of miR-885-5p in OS remains unknown. In the present study, it was found that the expression of miR-885-5p was markedly upregulated in OS cell lines and clinical tissues. Moreover, high expression of miR-885-5p was significantly associated with the development of OS. The human OS MG-63 cell line was transfected with recombinant lentivirus to regulate miR-885-5p expression. Overexpressed miR-885-5p significantly promoted the proliferation and migration of MG-63 cells in vitro, while downregulating miR-885-5p expression reversed these effects. Furthermore, bioinformatic analysis was used to predict the potential target genes of miR-885-5p, and cell division cycle protein 73 homolog (CDC73) was identified as a novel and direct target of miR-885-5p. This interaction was further confirmed using reverse transcription-quantitative polymerase chain reaction, western blotting and luciferase activity assays. These findings suggest that miR-885-5p serves a critical role in facilitating OS proliferation and migration, and can regulate CDC73 expression in OS cells and tissues. Thus, miR-885-5p could be a promising novel therapeutic biomarker for OS.
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Affiliation(s)
- Feng-Qiang Yu
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Zeng Wang
- Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Xin-Wen Wang
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Sheng-Lin Wang
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Xiao-Dong Li
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Qing-Shan Huang
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Jian-Hua Lin
- Department of Orthopedics, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China.,Central Laboratory, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
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18
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Ranjbar R, Hesari A, Ghasemi F, Sahebkar A. Expression of microRNAs and IRAK1 pathway genes are altered in gastric cancer patients with Helicobacter pylori infection. J Cell Biochem 2018; 119:7570-7576. [PMID: 29797599 DOI: 10.1002/jcb.27067] [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: 11/05/2017] [Accepted: 04/23/2018] [Indexed: 12/12/2022]
Abstract
Gastric cancer (GC) is among the most common cancer types in the world and one of the most lethal gastrointestinal cancers. MicroRNAs (miRNAs) can be of great importance in the early detection of GC. This study aimed to investigate some miRNAs and the genes involved in IRAK1 pathways in the serum of GC patients with Helicobacter pylori (H. pylori) infections compared to the control group. Total RNA was extracted from the serum of GC patients with H. pylori infection and healthy volunteers. The expression levels of miRNAs and the genes were assessed using Real time RT-PCR with specific primers. Our data showed that miR-146, miR-375, and Let-7 were down-regulated and miR-19 and miR-21 were up-regulated in GC patients with H. pylori infection. Other genes involved in the pathways such as RAS, MYC, NFKB, JUN, TRAF6, and IRAK4 were overexpressed; while the expression of PTEN gene was decreased compared to the control group. Expression of miRNAs and IRAK1 pathway genes are altered in patients with GC and H. pylori infection. This suggests a potential role for the above-mentioned miRNAs and genes in the diagnosis of GC.
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Affiliation(s)
- Reza Ranjbar
- Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - AmirReza Hesari
- Molecular Biology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Faezeh Ghasemi
- Department of Biotechnology, School of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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19
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Wang Y, Zhao S, Zhu L, Zhang Q, Ren Y. MiR-19a negatively regulated the expression of PTEN and promoted the growth of ovarian cancer cells. Gene 2018; 670:166-173. [PMID: 29783075 DOI: 10.1016/j.gene.2018.05.063] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 05/12/2018] [Accepted: 05/16/2018] [Indexed: 12/12/2022]
Abstract
Ovarian cancer is the most lethal malignancy of the women genital tract. Exploring novel factors involved in the development of ovarian cancer and characterizing the molecular mechanisms by which regulate the tumorigenesis of ovarian cancer are quite necessary. Here, we found that miR-19a was highly expressed in ovarian cancer tissues and cell lines. Overexpression of miR-19a promoted the viability of ovarian cancer cells, while down-regulation of miR-19a inhibited the growth of ovarian cancer cells. To further understand the underlying molecular mechanism of miR-19a in regulating ovarian cancer cell growth, the downstream targets of miR-19a were predicted. The bioinformatics analysis showed that the tumor suppressor PTEN was found as one of the targeting candidates of miR-19a. MiR-19a bound the 3'-UTR of PTEN and highly expressed miR-19a decreased both the mRNA and protein levels of PTEN in ovarian cancer cells. Overexpression of PTEN suppressed the promoting effect of miR-19a on regulating the growth of ovarian cancer cells. Notably, the expression of miR-19a and PTEN was inversely correlated in ovarian cancer tissues. These results demonstrated the potential oncogenic role of miR-19a in ovarian cancer, which suggested that miR-19a might be a promising target in the diagnosis and treatment of ovarian cancer.
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Affiliation(s)
- Yuhong Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang City 453100, China.
| | - Shuzhen Zhao
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang City 453100, China
| | - Lihong Zhu
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang City 453100, China
| | - Quanle Zhang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang City 453100, China
| | - Yanfang Ren
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Xinxiang City 453100, China
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20
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Yin Z, Yang J, Ning R, Liu Y, Feng M, Gu C, Fei J, Li Y. Signal pathways, diseases, and functions associated with the miR-19a/92a cluster and the use of berberine to modulate the expression of this cluster in multiple myeloma cells. J Biochem Mol Toxicol 2018; 32:e22057. [PMID: 29687521 DOI: 10.1002/jbt.22057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 03/27/2018] [Accepted: 04/02/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Berberine downregulated miR-19a/92a cluster expression in multiple myeloma (MM) cells. METHODS The cell viability of MM cells after berberine treatment was measured by CCK8 assay. qRT-PCR assay validated miR-19a/92a expression in multiple myeloma cells. TAM database analyzed miR-19a/92a-associated disease. miREnvironment database revealed that effects of environmental factors on the miR-19a/92a cluster. By targeting the seed region in the miRNA, the role of t-anti-miR-19a/92a cluster was evaluated by cell proliferation, migration, and colony formation. RESULTS Berberine inhibited the cell viability of MM cells and downregulated the expression of miR-19a/92a. Seven kinds of hematological malignancies are closely associated with miR-19a/92a expression. By targeting the seed region of the miRNA, t-anti-miR-19a/92a significantly inhibits multiple myeloma cell proliferation, migration, and colony formation. CONCLUSION Our findings may exhibit that miR-19a/92a cluster is a therapeutic target for MM and provide new mechanistic insight into the anti-MM effects of certain compounds in traditional Chinese herbal medicines.
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Affiliation(s)
- Zhao Yin
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.,Antisense Biopharmaceutical technology co., Ltd., Guangzhou, China
| | - Juhua Yang
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China
| | - Rong Ning
- Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Yanjun Liu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China
| | - Maoxiao Feng
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China
| | - Chunmin Gu
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Jia Fei
- Department of Biochemistry and Molecular Biology, Medical College of Jinan University, 601 Western Huangpu Avenue, 510632, Guangzhou, China.,Engineering Technology Research Center of drug development for small nucleic acid, Guangdong, China.,Institute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China.,Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China
| | - Yumin Li
- Antisense Biopharmaceutical technology co., Ltd., Guangzhou, China.,Medical Laboratory of Shen zhen Luohu People's Hospital
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MicroRNA-19a and microRNA-19b promote the malignancy of clear cell renal cell carcinoma through targeting the tumor suppressor RhoB. PLoS One 2018; 13:e0192790. [PMID: 29474434 PMCID: PMC5825063 DOI: 10.1371/journal.pone.0192790] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/30/2018] [Indexed: 01/02/2023] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma, which shows high aggressiveness and lacks biomarkers. RhoB acts as a tumor suppressor that inhibits the progression of ccRCC. In the present study, we examined the effects of oncogenic microRNAs, miR-19a and miR-19b, on RhoB expression in ccRCC cells. The results showed that both miR-19a and miR-19b could directly target the 3′untranslated region (3’UTR) of RhoB, resulting in the reduced expression of RhoB. With RT-PCR analysis, we detected the increased expression of miR-19a and miR-19b in ccRCC tissues compared to adjacent non-tumor renal tissues. These data also demonstrated an exclusive negative correlation between miR-19a/19b and RhoB expression in ccRCC specimens and cell lines. In addition, the knockdown of RhoB or overexpression of miR-19a and miR-19b in ccRCC cells could promote cell proliferation, migration and invasion. These data demonstrate the direct roles of miR-19a and miR-19b on the repression of RhoB and its consequences on tumorigenesis, cancer cell proliferation and invasiveness. These results suggest the potential clinical impact of miR-19a and miR-19b as molecular targets for ccRCC.
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22
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Jin HY, Oda H, Chen P, Yang C, Zhou X, Kang SG, Valentine E, Kefauver JM, Liao L, Zhang Y, Gonzalez-Martin A, Shepherd J, Morgan GJ, Mondala TS, Head SR, Kim PH, Xiao N, Fu G, Liu WH, Han J, Williamson JR, Xiao C. Differential Sensitivity of Target Genes to Translational Repression by miR-17~92. PLoS Genet 2017; 13:e1006623. [PMID: 28241004 PMCID: PMC5348049 DOI: 10.1371/journal.pgen.1006623] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 03/13/2017] [Accepted: 02/08/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are thought to exert their functions by modulating the expression of hundreds of target genes and each to a small degree, but it remains unclear how small changes in hundreds of target genes are translated into the specific function of a miRNA. Here, we conducted an integrated analysis of transcriptome and translatome of primary B cells from mutant mice expressing miR-17~92 at three different levels to address this issue. We found that target genes exhibit differential sensitivity to miRNA suppression and that only a small fraction of target genes are actually suppressed by a given concentration of miRNA under physiological conditions. Transgenic expression and deletion of the same miRNA gene regulate largely distinct sets of target genes. miR-17~92 controls target gene expression mainly through translational repression and 5’UTR plays an important role in regulating target gene sensitivity to miRNA suppression. These findings provide molecular insights into a model in which miRNAs exert their specific functions through a small number of key target genes. MicroRNAs (miRNAs) are small RNAs encoded by our genome. Each miRNA binds hundreds of target mRNAs and performs specific functions. It is thought that miRNAs exert their function by reducing the expression of all these target genes and each to a small degree. However, these target genes often have very diverse functions. It has been unclear how small changes in hundreds of target genes with diverse functions are translated into the specific function of a miRNA. Here we take advantage of recent technical advances to globally examine the mRNA and protein levels of 868 target genes regulated by miR-17~92, the first oncogenic miRNA, in mutant mice with transgenic overexpression or deletion of this miRNA gene. We show that miR-17~92 regulates target gene expression mainly at the protein level, with little effect on mRNA. Surprisingly, only a small fraction of target genes respond to miR-17~92 expression changes. Further studies show that the sensitivity of target genes to miR-17~92 is determined by a non-coding region of target mRNA. Our findings demonstrate that not every target gene is equal, and suggest that the function of a miRNA is mediated by a small number of key target genes.
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Affiliation(s)
- Hyun Yong Jin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Hiroyo Oda
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pengda Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Chao Yang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xiaojuan Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Seung Goo Kang
- Division of Biomedical Convergence/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Elizabeth Valentine
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jennifer M. Kefauver
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- Kellogg School of Science and Technology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Lujian Liao
- Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), School of Life Sciences, East China Normal University, Shanghai, China
| | - Yaoyang Zhang
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
| | - Alicia Gonzalez-Martin
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Jovan Shepherd
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
| | - Gareth J. Morgan
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California, United States of America
| | - Tony S. Mondala
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Steven R. Head
- Next Generation Sequencing Core, The Scripps Research Institute, La Jolla, California, United States of America
| | - Pyeung-Hyeun Kim
- Department of Molecular Bioscience/Institute of Bioscience & Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon, Republic of Korea
| | - Nengming Xiao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Guo Fu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Wen-Hsien Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Jiahuai Han
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - James R. Williamson
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, United States of America
| | - Changchun Xiao
- Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- * E-mail:
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Ma Q, Peng Z, Wang L, Li Y, Wang K, Zheng J, Liang Z, Liu T. miR-19a correlates with poor prognosis of clear cell renal cell carcinoma patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Int J Oncol 2016; 49:2589-2599. [DOI: 10.3892/ijo.2016.3746] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 10/10/2016] [Indexed: 11/06/2022] Open
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24
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da Silva Oliveira KC, Thomaz Araújo TM, Albuquerque CI, Barata GA, Gigek CO, Leal MF, Wisnieski F, Rodrigues Mello Junior FA, Khayat AS, de Assumpção PP, Rodriguez Burbano RM, Smith MC, Calcagno DQ. Role of miRNAs and their potential to be useful as diagnostic and prognostic biomarkers in gastric cancer. World J Gastroenterol 2016; 22:7951-7962. [PMID: 27672290 PMCID: PMC5028809 DOI: 10.3748/wjg.v22.i35.7951] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 06/14/2016] [Accepted: 08/01/2016] [Indexed: 02/06/2023] Open
Abstract
Alterations in epigenetic control of gene expression play an important role in many diseases, including gastric cancer. Many studies have identified a large number of upregulated oncogenic miRNAs and downregulated tumour-suppressor miRNAs in this type of cancer. In this review, we provide an overview of the role of miRNAs, pointing to their potential to be useful as diagnostic and/or prognostic biomarkers in gastric cancer. Moreover, we discuss the influence of polymorphisms and epigenetic modifications on miRNA activity.
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25
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Hu W, Jin P, Ding C, Liu W. miR-19a/b modulates lung cancer cells metastasis through suppression of MXD1 expression. Oncol Lett 2016; 12:1901-1905. [PMID: 27588137 PMCID: PMC4998008 DOI: 10.3892/ol.2016.4881] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 07/19/2016] [Indexed: 12/31/2022] Open
Abstract
Increasing evidence has shown that microRNA (miRNA) is extensively involved in the pathophysiology of lung cancer. Microarray data demonstrated the increasing levels of miR-19a in the peripheral blood from patients suffering from lung cancer, which is closely associated with poor prognosis of lung cancer. However, the underlying molecular mechanism of miR-19a remains to be determined. The results of the present study showed a higher expression of miR-19a compared with normal bronchial epithelial cells. Furthermore, lentivirus vectors were constructed to establish cell lines that overexpressed and knocked out miR-19a in order to study the role of miR-19a on the metastasis and proliferation of lung cancer cells. Investigation into the underlying mechanism of miR-19a, revealed that MXD1 may be the key gene targeting miR-19a, participating in the process of proliferation and metastasis of lung cancer cells.
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Affiliation(s)
- Wenxia Hu
- Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050012, P.R. China
| | - Pule Jin
- Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050012, P.R. China
| | - Cuimin Ding
- Department of Respiratory Medicine, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050012, P.R. China
| | - Wei Liu
- Department of Oncology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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26
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MiR-19a promotes cell proliferation and invasion by targeting RhoB in human glioma cells. Neurosci Lett 2016; 628:161-6. [PMID: 27329239 DOI: 10.1016/j.neulet.2016.06.031] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2016] [Revised: 06/06/2016] [Accepted: 06/17/2016] [Indexed: 01/30/2023]
Abstract
MicroRNA-19a (miR-19a) is upregulated in different types of cancers, including gliomas, but its specific role and function in gliomas have yet to be fully elucidated. In this study, we found that miR-19a was significantly upregulated in human glioma tissues and cell lines. Overexpression of miR-19a by a miR-19a mimic promoted glioma cell proliferation and invasion. In contrast, miR-19a inhibitor suppressed cell proliferation and invasion. Furthermore, by a dual-luciferase reporter assay and expression analysis, we determined that Ras homolog family member B was a direct target of miR-19a. Knockdown of Ras homolog family member B could block cell proliferation and invasion induced by the miR-19a mimic. In conclusion, our study demonstrated that miR-19a upregulation is common in gliomas and that suppression of miR-19a expression inhibits cell proliferation and invasion, which indicates that miR-19a may act as an oncogene in gliomas.
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27
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Effect of miR-19a and miR-21 on the JAK/STAT signaling pathway in the peripheral blood mononuclear cells of patients with systemic juvenile idiopathic arthritis. Exp Ther Med 2016; 11:2531-2536. [PMID: 27284344 DOI: 10.3892/etm.2016.3188] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/11/2016] [Indexed: 12/14/2022] Open
Abstract
Overexpression of the components of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway are key factors of the pathogenic mechanisms underlying systematic juvenile idiopathic arthritis (SJIA). The present study aimed to investigate the association between microRNA (miR)-19a, miR-21 and the JAK/STAT signaling pathway. A total of 20 patients with SJIA were included in the study, and peripheral blood mononuclear cells (PBMCs) from 20 normal controls were also collected. RNAiso was used to extract total RNA, and the RNA was then reverse transcribed into cDNA. Primers were designed to detect the mRNA of miR-19a and miR-21, and U6 was set as the internal parameter. In addition, the mRNA of STAT3, suppressor of cytokine signaling 3 (SOCS3), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) was detected, and β-actin was set as the internal parameter. Reverse transcription-quantitative polymerase chain reaction was performed to detect the expression levels of these proteins in patients with SJIA and control subjects, and non-parametric tests were used to analyze the statistical differences in 2-ΔΔCq between the two groups. The expression levels of miR-19a and miR-21 were significantly lower in the SJIA group compared with the control group (P<0.05). SOCS3, TNF-α and STAT3 were shown to be the target genes of miR-19a and miR-21, as determined by Targetscan. The expression levels of STAT3, SOCS3, TNF-α and IL-6 mRNA were significantly higher compared with those of the control group (P<0.05). In the PBMCs of sthe patients with SJIA, miR-19a and miR-21 expression levels were lower compared with those of the control group, and the JAK/STAT signaling pathway was activated, which indicated that miR-19a and miR-21 may participate in the activation of the JAK/STAT signaling pathway.
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28
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Samadi AK, Bilsland A, Georgakilas AG, Amedei A, Amin A, Bishayee A, Azmi AS, Lokeshwar BL, Grue B, Panis C, Boosani CS, Poudyal D, Stafforini DM, Bhakta D, Niccolai E, Guha G, Vasantha Rupasinghe HP, Fujii H, Honoki K, Mehta K, Aquilano K, Lowe L, Hofseth LJ, Ricciardiello L, Ciriolo MR, Singh N, Whelan RL, Chaturvedi R, Ashraf SS, Shantha Kumara HMC, Nowsheen S, Mohammed SI, Keith WN, Helferich WG, Yang X. A multi-targeted approach to suppress tumor-promoting inflammation. Semin Cancer Biol 2015; 35 Suppl:S151-S184. [PMID: 25951989 PMCID: PMC4635070 DOI: 10.1016/j.semcancer.2015.03.006] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Revised: 03/13/2015] [Accepted: 03/16/2015] [Indexed: 12/15/2022]
Abstract
Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes.
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Affiliation(s)
| | - Alan Bilsland
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
| | - Alexandros G Georgakilas
- Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
| | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Amr Amin
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates; Faculty of Science, Cairo University, Cairo, Egypt
| | - Anupam Bishayee
- Department of Pharmaceutical Sciences, College of Pharmacy, Larkin Health Sciences Institute, Miami, FL, United States
| | - Asfar S Azmi
- Department of Pathology, Wayne State Univeristy, Karmanos Cancer Center, Detroit, MI, USA
| | - Bal L Lokeshwar
- Department of Urology, University of Miami, Miller School of Medicine, Miami, FL, United States; Miami Veterans Administration Medical Center, Miami, FL, United States
| | - Brendan Grue
- Department of Environmental Science, Dalhousie University, Halifax, Nova Scotia, Canada; Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Carolina Panis
- Laboratory of Inflammatory Mediators, State University of West Paraná, UNIOESTE, Paraná, Brazil
| | - Chandra S Boosani
- Department of BioMedical Sciences, School of Medicine, Creighton University, Omaha, NE, United States
| | - Deepak Poudyal
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, United States
| | - Diana M Stafforini
- Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Dipita Bhakta
- School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | | | - Gunjan Guha
- School of Chemical and Biotechnology, SASTRA University, Thanjavur, Tamil Nadu, India
| | - H P Vasantha Rupasinghe
- Department of Environmental Sciences, Faculty of Agriculture and Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Hiromasa Fujii
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Kanya Honoki
- Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan
| | - Kapil Mehta
- Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Katia Aquilano
- Department of Biology, University of Rome "Tor Vergata", Rome, Italy
| | - Leroy Lowe
- Getting to Know Cancer, Truro, Nova Scotia, Canada.
| | - Lorne J Hofseth
- Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, United States
| | - Luigi Ricciardiello
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | | | - Neetu Singh
- Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Richard L Whelan
- Department of Surgery, St. Luke's Roosevelt Hospital, New York, NY, United States
| | - Rupesh Chaturvedi
- School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
| | - S Salman Ashraf
- Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
| | - H M C Shantha Kumara
- Department of Surgery, St. Luke's Roosevelt Hospital, New York, NY, United States
| | - Somaira Nowsheen
- Medical Scientist Training Program, Mayo Graduate School, Mayo Medical School, Mayo Clinic, Rochester, MN, United States
| | - Sulma I Mohammed
- Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, IN, United States
| | - W Nicol Keith
- Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK
| | | | - Xujuan Yang
- University of Illinois at Urbana Champaign, Champaign, IL, United States
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29
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Lui PY, Jin DY, Stevenson NJ. MicroRNA: master controllers of intracellular signaling pathways. Cell Mol Life Sci 2015; 72:3531-42. [PMID: 26059472 PMCID: PMC11113591 DOI: 10.1007/s00018-015-1940-0] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 05/05/2015] [Accepted: 05/26/2015] [Indexed: 12/20/2022]
Abstract
Signaling pathways are essential intracellular networks that coordinate molecular outcomes to external stimuli. Tight regulation of these pathways is essential to ensure an appropriate response. MicroRNA (miRNA) is a class of small, non-coding RNA that regulates gene expression at a post-transcriptional level by binding to the complementary sequence on target mRNA, thus limiting protein translation. Intracellular pathways are controlled by protein regulators, such as suppressor of cytokine signaling and A20. Until recently, expression of these classical protein regulators was thought to be controlled solely by transcriptional induction and proteasomal degradation; however, there is a growing body of evidence describing their regulation by miRNA. This new information has transformed our understanding of cell signaling by adding a previously unknown layer of regulatory control. This review outlines the miRNA regulation of these classical protein regulators and describes their broad effects at both cellular and disease levels. We review the regulation of three important signaling pathways, including the JAK/STAT, NF-κB, and TGF-β pathways, and summarize an extensive catalog of their regulating miRNAs. This information highlights the importance of the miRNA regulon and reveals a previously unknown regulatory landscape that must be included in the identification and development of novel therapeutic targets for clinical disorders.
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Affiliation(s)
- Pak-Yin Lui
- Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong
| | - Dong-Yan Jin
- Department of Biochemistry, The University of Hong Kong, Pokfulam, Hong Kong
| | - Nigel J. Stevenson
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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30
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Tan Y, Yin H, Zhang H, Fang J, Zheng W, Li D, Li Y, Cao W, Sun C, Liang Y, Zeng J, Zou H, Fu W, Yang X. Sp1-driven up-regulation of miR-19a decreases RHOB and promotes pancreatic cancer. Oncotarget 2015; 6:17391-403. [PMID: 26041879 PMCID: PMC4627316 DOI: 10.18632/oncotarget.3975] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 05/13/2015] [Indexed: 01/20/2023] Open
Abstract
Cancer treatment alters microRNA (miRNA) expression, revealing potential therapeutic targets (oncotarget). Here we treated pancreatic cancer (ASPC-1) cells with either recombinant human endostatin (rh-endostatin) or gemcitabine. Then high-throughput sequencing assay was performed to screen for altered miRNAs. Both treatments decreased levels of MiR-19a. We found that miR-19a stimulated cell proliferation, migration, invasion in vitro and tumor growth in vivo. High levels of miR-19a correlated with poor prognosis in patients. Ras homolog family member B (RHOB) was identified as a direct target of miR-19a. Furthermore, RHOB was down-regulated in human pancreatic cancer samples. Restoration of RHOB induced apoptosis, inhibited proliferation and migration of ASPC-1 cells. SP-1 was identified as an upstream transcription factor of miR-19a gene, promoting miR-19a transcription. Rh-endostatin decreased miR-19a expression by down-regulating SP-1. These findings suggest that miR-19a is a potential therapeutic target in pancreatic cancer.
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Affiliation(s)
- Yonggang Tan
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Hongzhuan Yin
- Department of General Surgery, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Heying Zhang
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Jun Fang
- Laboratory of Microbiology & Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan
| | - Wei Zheng
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Dan Li
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Yue Li
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Wei Cao
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Cheng Sun
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Yusi Liang
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Juan Zeng
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Huawei Zou
- Department of Oncology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
| | - Weineng Fu
- Department of Medical Genetics, China Medical University, Shenyang, P.R. China
| | - Xianghong Yang
- Department of Pathology, Shengjing Hospital, China Medical University, Shenyang, P.R. China
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31
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Jiang C, Chen X, Alattar M, Wei J, Liu H. MicroRNAs in tumorigenesis, metastasis, diagnosis and prognosis of gastric cancer. Cancer Gene Ther 2015; 22:291-301. [DOI: 10.1038/cgt.2015.19] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 03/15/2015] [Accepted: 03/16/2015] [Indexed: 02/07/2023]
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Jiang WL, Zhang YF, Xia QQ, Zhu J, Yu X, Fan T, Wang F. MicroRNA-19a regulates lipopolysaccharide-induced endothelial cell apoptosis through modulation of apoptosis signal-regulating kinase 1 expression. BMC Mol Biol 2015; 16:11. [PMID: 25982447 PMCID: PMC4446110 DOI: 10.1186/s12867-015-0034-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 02/19/2015] [Indexed: 01/07/2023] Open
Abstract
Background MicroRNAs, small non-encoding RNAs that post-transcriptionally modulate expression of their target genes, have been implicated as critical regulatory molecules in endothelial cells. Results In the present study, we found that overexpression of miR-19a protects endothelial cells from lipopolysaccharide (LPS)-induced apoptosis through the apoptosis signal-regulating kinase 1 (ASK1)/p38 pathway. Quantitative real-time PCR demonstrated that the expression of miR-19a in endothelial cell was markedly down-regulated by LPS stimulation. Furthermore, LPS-induced apoptosis was significantly inhibited by over-expression of miR-19a. Finally, both a luciferase reporter assay and western blot analysis showed that ASK1 is a direct target of miR-19a. Conclusions MiR-19a regulates ASK1 expression by targeting specific binding sites in the 3’ untranslated region of ASK1 mRNA. Overexpression of miR-19a is an effective method to protect against LPS-induced apoptosis of endothelial cells. Electronic supplementary material The online version of this article (doi:10.1186/s12867-015-0034-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wei-Long Jiang
- Department of Respiration, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Yu-Feng Zhang
- Department of Respiration, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Qing-Qing Xia
- Department of Respiration, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Jian Zhu
- Department of Neurology, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Xin Yu
- Department of Internal Medicine, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Tao Fan
- Department of Neurology, Jiangyin Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Jiangyin City, Jiangsu Province, 214400, China.
| | - Feng Wang
- Department of Neurology, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
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Lu WD, Zuo Y, Xu Z, Zhang M. MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer. World J Gastroenterol 2015; 21:4564-4573. [PMID: 25914465 PMCID: PMC4402303 DOI: 10.3748/wjg.v21.i15.4564] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/04/2014] [Accepted: 12/08/2014] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the mechanism by which miR-19a is up-regulated in gastric cancer (GC), which plays an oncogenic role.
METHODS: In the present study, we investigated the role of miR-19a in gastric tissues as well as two GC cell lines. In vivo, we detected the basal expression level of miR-19a using real-time reverse transcription-PCR (RT-PCR), and the relevance between expression of miR-19a and clinicopathological information was analyzed. In vitro, miR-19a was ectopically expressed using overexpression and knock-down strategies.
RESULTS: Overexpression of miR-19a was significantly associated with metastasis of GC and inferior overall prognosis. However, no significant correlation was found between miR-19a expression and other characteristics such as age, gender, tobacco, alcohol or tumor size. Cell proliferation, migration and invasion assays showed that overexpression of miR-19a promoted the proliferation, migration and invasion, and that overexpression of miR-19a promoted the epithelial-mesenchymal transition through activating the PI3K/AKT pathway. Blocking the PI3K/AKT pathway could cancel the effect of miR-19a.
CONCLUSION: All together, our results suggest that miR-19a could be used as a promising therapeutic target in the treatment of GC.
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Al-Jamal HAN, Jusoh SAM, Yong AC, Asan JM, Hassan R, Johan MF. Silencing of suppressor of cytokine signaling-3 due to methylation results in phosphorylation of STAT3 in imatinib resistant BCR-ABL positive chronic myeloid leukemia cells. Asian Pac J Cancer Prev 2015; 15:4555-61. [PMID: 24969884 DOI: 10.7314/apjcp.2014.15.11.4555] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Silencing due to methylation of suppressor of cytokine signaling-3 (SOCS-3), a negative regulator gene for the JAK/STAT signaling pathway has been reported to play important roles in leukemogenesis. Imatinib mesylate is a tyrosine kinase inhibitor that specifically targets the BCR-ABL protein and induces hematological remission in patients with chronic myeloid leukemia (CML). Unfortunately, the majority of CML patients treated with imatinib develop resistance under prolonged therapy. We here investigated the methylation profile of SOCS-3 gene and its downstream effects in a BCR-ABL positive CML cells resistant to imatinib. MATERIALS AND METHODS BCR-ABL positive CML cells resistant to imatinib (K562-R) were developed by overexposure of K562 cell lines to the drug. Cytotoxicity was determined by MTS assays and IC50 values calculated. Apoptosis assays were performed using annexin V-FITC binding assays and analyzed by flow cytometry. Methylation profiles were investigated using methylation specific PCR and sequencing analysis of SOCS-1 and SOCS-3 genes. Gene expression was assessed by quantitative real-time PCR, and protein expression and phosphorylation of STAT1, 2 and 3 were examined by Western blotting. RESULTS The IC50 for imatinib on K562 was 362 nM compared to 3,952 nM for K562-R (p=0.001). Percentage of apoptotic cells in K562 increased upto 50% by increasing the concentration of imatinib, in contrast to only 20% in K562-R (p<0.001). A change from non-methylation of the SOCS-3 gene in K562 to complete methylation in K562-R was observed. Gene expression revealed down- regulation of both SOCS-1 and SOCS-3 genes in resistant cells. STAT3 was phosphorylated in K562-R but not K562. CONCLUSIONS Development of cells resistant to imatinib is feasible by overexposure of the drug to the cells. Activation of STAT3 protein leads to uncontrolled cell proliferation in imatinib resistant BCR-ABL due to DNA methylation of the SOCS-3 gene. Thus SOCS-3 provides a suitable candidate for mechanisms underlying the development of imatinib resistant in CML patients.
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Affiliation(s)
- Hamid A N Al-Jamal
- Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail :
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Wan X, Ding X, Chen S, Song H, Jiang H, Fang Y, Li P, Guo J. The functional sites of miRNAs and lncRNAs in gastric carcinogenesis. Tumour Biol 2015; 36:521-32. [PMID: 25636450 PMCID: PMC4342515 DOI: 10.1007/s13277-015-3136-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 01/19/2015] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of the most common malignant diseases and has one of the highest mortality rates worldwide. Its molecular mechanisms are poorly understood. Recently, the functions of non-coding RNAs (ncRNAs) in gastric cancer have attracted wide attention. Although the expression levels of various ncRNAs are different, they may work together in a network and contribute to gastric carcinogenesis by altering the expression of oncogenes or tumor suppressor genes. They affect the cell cycle, apoptosis, motility, invasion, and metastasis. Dysregulated microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), including miR-21, miR-106, H19, and ANRIL, directly or indirectly regulate carcinogenic factors or signaling pathways such as PTEN, CDK, caspase, E-cadherin, Akt, and P53. Greater recognition of the roles of miRNAs and lncRNAs in gastric carcinogenesis can provide new insight into the mechanisms of tumor development and identify targets for anticancer drug development.
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Affiliation(s)
- Xiangxiang Wan
- Department of Gastroenterology, Ningbo First Hospital, No. 59 Liuting Street, Ningbo, 315010, China
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Let-7b inhibits cell proliferation, migration, and invasion through targeting Cthrc1 in gastric cancer. Tumour Biol 2014; 36:3221-9. [PMID: 25510669 DOI: 10.1007/s13277-014-2950-5] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 12/04/2014] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of specific microRNAs (miRNAs) is found to play a vital role in carcinogenesis and progression of gastric cancer (GC). In the present study, we investigated the expression profiles of miRNAs in gastric cancer. Let-7b was found downregulated remarkably in gastric cancer tissues and was correlated with Helicobacter pylori infection, tumor stage, and lymphatic metastasis. Ectopic expression of let-7b suppressed the growth, migration, invasion, and tumorigenicity of GC cells, whereas let-7b knockdown promoted these phenotypes. Bioinformatic analysis predicted collagen triple helix repeat containing 1 (Cthrc1) as a direct target of let-7b. Luciferase assay showed that let-7b repressed the activity of Cthrc1 through binding its 3'UTR. Western blotting also confirmed that the protein levels of Cthrc1 were decreased by let-7b. Cthrc1 was significantly upregulated and reversely correlated with let-7b levels in GC. Co-expression of let-7b and Cthrc1 without its 3'UTR could rescue cell growth, migration, and invasion inhibited by let-7b. These results suggest that let-7b may directly target Cthrc1 and function as a tumor suppressor gene in GC.
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Tang Y, Liu X, Su B, Zhang Z, Zeng X, Lei Y, Shan J, Wu Y, Tang H, Su Q. microRNA-22 acts as a metastasis suppressor by targeting metadherin in gastric cancer. Mol Med Rep 2014; 11:454-60. [PMID: 25323629 DOI: 10.3892/mmr.2014.2682] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Accepted: 08/29/2014] [Indexed: 11/06/2022] Open
Abstract
microRNA (miR)-22 has been reported to be downregulated in hepatocellular, lung, colorectal, ovarian and breast cancer, acting as a tumor suppressor. The present study investigated the potential effects of miR-22 on gastric cancer invasion and metastasis and the molecular mechanism. miR-22 expression was examined in tumor tissues of in 89 gastric cancer patients by in situ hybridization (ISH) analysis. Additionally, the association between miR-22 levels and clinicopathological parameters was analyzed. A luciferase assay was conducted for target identification. The ability of invasion and metastasis of gastric cancer cells in vitro and in vivo was evaluated by cell migration and invasion assays and in a xenograft model. The results showed that miR-22 was downregulated in the gastric cancer specimens and significantly correlated with the advanced clinical stage and lymph node metastasis. In addition, metadherin (MTDH) was shown to be a direct target of miR-22 and the expression of MTDH was inversely correlated with miR-22 expression in gastric cancer. Ectopic expression of miR-22 suppressed cell invasion and metastasis in vitro and in vivo. The present study suggested that miR-22 may be a valuable prognostic factor in gastric cancer. miR-22 inhibited gastric cancer cell invasion and metastasis by directly targeting MTDH. The novel miR-22/MTDH link confirmed in the present study provided a novel, potential therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Yunyun Tang
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xiaoping Liu
- Sun Yat‑Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Bo Su
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Zhiwei Zhang
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Xi Zeng
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yanping Lei
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Jian Shan
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Yongjun Wu
- Cancer Research Institute, University of South China, Key Laboratory of Cancer Cellular and Molecular Pathology of Hunan Provincial University, Hengyang, Hunan 421001, P.R. China
| | - Hailin Tang
- Sun Yat‑Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
| | - Qi Su
- Center for Gastric Cancer Research of Hunan Province, First Affiliated Hospital, University of South China, Hengyang, Hunan 421001, P.R. China
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LI HAILONG, XIE SHOUPIN, LIU XIAOJUN, WU HONGYAN, LIN XINGYAO, GU JING, WANG HUPING, DUAN YONGQIANG. Matrine alters microRNA expression profiles in SGC-7901 human gastric cancer cells. Oncol Rep 2014. [DOI: 10.3892/or_xxxxxxxx] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
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Jin J, Cai L, Liu ZM, Zhou XS. miRNA-218 inhibits osteosarcoma cell migration and invasion by down-regulating of TIAM1, MMP2 and MMP9. Asian Pac J Cancer Prev 2014; 14:3681-4. [PMID: 23886165 DOI: 10.7314/apjcp.2013.14.6.3681] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Deregulated miRNAs participate in osteosarcoma genesis. In this study, the expression of miRNA-218 in human osteosarcomas, adjacent normal tissues and Saos-2 human osteosarcoma cells was first assessed. Then the precise role of miRNA-218 in osteosarcoma cells was investigated. Upon transfection with a miR-218 expression vector, the proliferation of Saos-2 human osteosarcoma cells determined using the ATPlite assay was significantly suppressed, whilw migration of Saos-2 cells detected by wound healing and invasion determined using transwells were dramatically inhibited. Potential target genes of miR-218 were predicted and T-cell lymphoma invasion and metastasis 1 (TIAM1) and matrix metalloproteinase 2 (MMP2) and 9 (MMP9) were identified. This was confirmed by western blotting, which showed that miR-218 expression inhibited TIAM1, MMP2 and MMP9 protein expression. Collectively, these data suggest that miR-218 acts as a tumor suppressor in osteosarcomas by down-regulating TIAM1, MMP2 and MMP9 expression.
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Affiliation(s)
- Jie Jin
- Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, China.
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Xia JT, Chen LZ, Jian WH, Wang KB, Yang YZ, He WL, He YL, Chen D, Li W. MicroRNA-362 induces cell proliferation and apoptosis resistance in gastric cancer by activation of NF-κB signaling. J Transl Med 2014; 12:33. [PMID: 24495516 PMCID: PMC3916099 DOI: 10.1186/1479-5876-12-33] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2013] [Accepted: 01/30/2014] [Indexed: 12/25/2022] Open
Abstract
Background According to cancer-related microRNA (miRNA) expression microarray research available in public databases, miR-362 expression is elevated in gastric cancer. However, the expression and biological role of miR-362 in gastric progression remain unclear. Methods miR-362 expression levels in gastric cancer tissues and cell lines were determined using real-time PCR. The roles of miR-362, in promoting gastric cancer cell proliferation and apoptosis resistance, were assessed by different biological assays, such as colony assay, flow cytometry and TUNEL assay. The effect of miR-362 on NF-κB activation was investigated using the luciferase reporter assay, fluorescent immunostaining. Results MiR-362 overexpression induced cell proliferation, colony formation, and resistance to cisplatin-induced apoptosis in BGC-823 and SGC-7901 gastric cancer cells. MiR-362 increased NF-κB activity and relative mRNA expression of NF-κB–regulated genes, and induced nuclear translocation of p65. Expression of the tumor suppressor CYLD was inhibited by miR-362 in gastric cancer cells; miR-362 levels were inversely correlated with CYLD expression in gastric cancer tissue. MiR-362 downregulated CYLD expression by binding its 3′ untranslated region. NF-κB activation was mechanistically associated with siRNA-mediated downregulation of CYLD. MiR-362 inhibitor reversed all the effects of miR-362. Conclusion The results suggest that miR-362 plays an important role in repressing the tumor suppressor CYLD and present a novel mechanism of miRNA-mediated NF-κB activation in gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | - De Chen
- Department of General Surgery, The third Affiliated Hospital, Guangzhou Medical University, #63 Duobao Road, Guangzhou, Guangdong 510150, China.
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