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Zhang JW, Zhang N, Lyu Y, Zhang XF. Influence of Sex in the Development of Liver Diseases. Semin Liver Dis 2025; 45:15-32. [PMID: 39809453 DOI: 10.1055/a-2516-0261] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The liver is a sexually dimorphic organ. Sex differences in prevalence, progression, prognosis, and treatment prevail in most liver diseases, and the mechanism of how liver diseases act differently among male versus female patients has not been fully elucidated. Biological sex differences in normal physiology and disease arise principally from sex hormones and/or sex chromosomes. Sex hormones contribute to the development and progression of most liver diseases, with estrogen- and androgen-mediated signaling pathways mechanistically involved. In addition, genetic factors in sex chromosomes have recently been found to contribute to the sex disparity of many liver diseases, which might explain, to some extent, the difference in gene expression pattern, immune response, and xenobiotic metabolism between men and women. Although increasing evidence suggests that sex is one of the most important modulators of disease prevalence and outcomes, at present, basic and clinical studies have long been sex unbalanced, with female subjects underestimated. As such, this review focuses on sex disparities of liver diseases and summarizes the current understanding of sex-specific mechanisms, including sex hormones, sex chromosomes, etc. We anticipate that understanding sex-specific pathogenesis will aid in promoting personalized therapies for liver disease among male versus female patients.
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Affiliation(s)
- Jie-Wen Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Nan Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Yi Lyu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
- National-Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi Province, People's Republic of China
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2
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Song H, Zhang Q, Fang G, Luo X, Wu D, Li H, Zhou K, Zhao X, Xu F, Zhang Y, Huang A. Unraveling the Mechanisms of MicroRNA in Suppressing Hepatitis B Virus Progression: A Comprehensive Review for Designing Treatment Strategies. HEPATITIS MONTHLY 2024; 24. [DOI: 10.5812/hepatmon-144239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 06/22/2024] [Accepted: 07/13/2024] [Indexed: 01/02/2025]
Abstract
: Liver cancer and cirrhosis caused by the Hepatitis B virus (HBV) remain significant global health challenges due to the virus's high prevalence and contagious nature. Hepatitis B virus can be transmitted through various means, leading to mild or severe liver disease. Although an effective prophylactic vaccine is available, it offers limited benefits for those already chronically infected. Current treatments often fail to consistently eliminate the virus and can cause severe adverse effects. In response to these challenges, researchers have begun exploring microRNAs (miRNAs) as novel therapeutic targets. Studying miRNA-virus interactions presents a promising opportunity to identify potential therapeutic targets. By manipulating host miRNAs, researchers aim to enhance antiviral defenses, restore cellular balance, and prevent viral replication. The text concludes by highlighting the potential for personalized medicine in Hepatitis B treatment, guided by individual miRNA profiles. Numerous studies have been conducted to understand how different miRNAs inhibit HBV replication, paving the way for the development of innovative and effective therapeutic strategies.
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Shi Y, Ma J, Li S, Liu C, Liu Y, Chen J, Liu N, Liu S, Huang H. Sex difference in human diseases: mechanistic insights and clinical implications. Signal Transduct Target Ther 2024; 9:238. [PMID: 39256355 PMCID: PMC11387494 DOI: 10.1038/s41392-024-01929-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 06/26/2024] [Accepted: 07/23/2024] [Indexed: 09/12/2024] Open
Abstract
Sex characteristics exhibit significant disparities in various human diseases, including prevalent cardiovascular diseases, cancers, metabolic disorders, autoimmune diseases, and neurodegenerative diseases. Risk profiles and pathological manifestations of these diseases exhibit notable variations between sexes. The underlying reasons for these sex disparities encompass multifactorial elements, such as physiology, genetics, and environment. Recent studies have shown that human body systems demonstrate sex-specific gene expression during critical developmental stages and gene editing processes. These genes, differentially expressed based on different sex, may be regulated by androgen or estrogen-responsive elements, thereby influencing the incidence and presentation of cardiovascular, oncological, metabolic, immune, and neurological diseases across sexes. However, despite the existence of sex differences in patients with human diseases, treatment guidelines predominantly rely on male data due to the underrepresentation of women in clinical trials. At present, there exists a substantial knowledge gap concerning sex-specific mechanisms and clinical treatments for diverse diseases. Therefore, this review aims to elucidate the advances of sex differences on human diseases by examining epidemiological factors, pathogenesis, and innovative progress of clinical treatments in accordance with the distinctive risk characteristics of each disease and provide a new theoretical and practical basis for further optimizing individualized treatment and improving patient prognosis.
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Affiliation(s)
- Yuncong Shi
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jianshuai Ma
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Sijin Li
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Chao Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Yuning Liu
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China
| | - Jie Chen
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ningning Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Shiming Liu
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
| | - Hui Huang
- Department of Cardiology, the Eighth Affiliated Hospital, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, Sun Yat-sen University, Shenzhen, China.
- Department of Cardiology, Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China.
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Li H, Jiang W, Liu S, Yang M, Chen S, Pan Y, Cui M. Connecting the mechanisms of tumor sex differences with cancer therapy. Mol Cell Biochem 2024; 479:213-231. [PMID: 37027097 DOI: 10.1007/s11010-023-04723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 03/26/2023] [Indexed: 04/08/2023]
Abstract
Sex differences in cancer incidence and survival are constant and pronounced globally, across all races and all age groups of cancer types. In 2016, after the National Institutes of Health proposed a policy of utilizing sex as a biological variable, researchers started paying more attention to the molecular mechanisms behind gender variations in cancer. Historically, most previous studies investigating sex differences have been centered on gonadal sex hormones. Nevertheless, sex differences also involve genetic and molecular pathways that run throughout the entire process of cancer cell proliferation, metastasis, and treatment response, in addition to sex hormones. In particular, there is significant gender dimorphism in the efficacy and toxicity of oncology treatments, including conventional radiotherapy and chemotherapy, as well as the emerging targeted therapies and immunotherapy. To be clear, not all mechanisms will exhibit gender bias, and not all gender bias will affect cancer risk. Our goal in this review is to discuss some of the significant sex-related changes in fundamental cancer pathways. To this purpose, we summarize the differential impact of gender on cancer development in three dimensions: sex hormones, genetics, and epigenetics, and focus on current hot subjects including tumor suppressor function, immunology, stem cell renewal, and non-coding RNAs. Clarifying the essential mechanisms of gender differences will help guide the clinical treatment of both sexes in tumor radiation and chemotherapy, medication therapy with various targets, immunotherapy, and even drug development. We anticipate that sex-differentiated research will help advance sex-based cancer personalized medicine models and encourage future basic scientific and clinical research to take sex into account.
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Affiliation(s)
- Huan Li
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Weibo Jiang
- Department of Orthopaedic, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Shui Liu
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Manshi Yang
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Siyuan Chen
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Yihan Pan
- The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China
| | - Mengying Cui
- Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun, 130041, People's Republic of China.
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Smiriglia A, Lorito N, Serra M, Perra A, Morandi A, Kowalik MA. Sex difference in liver diseases: How preclinical models help to dissect the sex-related mechanisms sustaining NAFLD and hepatocellular carcinoma. iScience 2023; 26:108363. [PMID: 38034347 PMCID: PMC10682354 DOI: 10.1016/j.isci.2023.108363] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2023] Open
Abstract
Only a few preclinical findings are confirmed in the clinic, posing a critical issue for clinical development. Therefore, identifying the best preclinical models can help to dissect molecular and mechanistic insights into liver disease pathogenesis while being clinically relevant. In this context, the sex relevance of most preclinical models has been only partially considered. This is particularly significant in NAFLD and HCC, which have a higher prevalence in men when compared to pre-menopause women but not to those in post-menopausal status, suggesting a role for sex hormones in the pathogenesis of the diseases. This review gathers the sex-relevant findings and the available preclinical models focusing on both in vitro and in vivo studies and discusses the potential implications and perspectives of introducing the sex effect in the selection of the best preclinical model. This is a critical aspect that would help to tailor personalized therapies based on sex.
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Affiliation(s)
- Alfredo Smiriglia
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Nicla Lorito
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marina Serra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Perra
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
| | - Andrea Morandi
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50134 Florence, Italy
| | - Marta Anna Kowalik
- Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy
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Nuermaimaiti A, Chang L, Yan Y, Sun H, Xiao Y, Song S, Feng K, Lu Z, Ji H, Wang L. The role of sex hormones and receptors in HBV infection and development of HBV-related HCC. J Med Virol 2023; 95:e29298. [PMID: 38087447 DOI: 10.1002/jmv.29298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 10/02/2023] [Accepted: 11/18/2023] [Indexed: 12/18/2023]
Abstract
Gender disparity in hepatitis B virus (HBV)-related diseases has been extensively documented. Epidemiological studies consistently reported that males have a higher prevalence of HBV infection and incidence of hepatocellular carcinoma (HCC). Further investigations have revealed that sex hormone-related signal transductions play a significant role in gender disparity. Sex hormone axes showed significantly different responses to virus entry and replication. The sex hormones axes change the HBV-specific immune responses and antitumor immunity. Additionally, Sex hormone axes showed different effects on the development of HBV-related disease. But the role of sex hormones remains controversial, and researchers have not reached a consensus on the role of sex hormones and the use of hormone therapies in HCC treatment. In this review, we aim to summarize the experimental findings on sex hormones and provide a comprehensive understanding of their roles in the development of HCC and their implications for hormone-related HCC treatment.
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Affiliation(s)
- Abudulimutailipu Nuermaimaiti
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Le Chang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Ying Yan
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huizhen Sun
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yingzi Xiao
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shi Song
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Kaihao Feng
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhuoqun Lu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Huimin Ji
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Lunan Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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7
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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8
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Caserta S, Gangemi S, Murdaca G, Allegra A. Gender Differences and miRNAs Expression in Cancer: Implications on Prognosis and Susceptibility. Int J Mol Sci 2023; 24:11544. [PMID: 37511303 PMCID: PMC10380791 DOI: 10.3390/ijms241411544] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 07/30/2023] Open
Abstract
MicroRNAs are small, noncoding molecules of about twenty-two nucleotides with crucial roles in both healthy and pathological cells. Their expression depends not only on genetic factors, but also on epigenetic mechanisms like genomic imprinting and inactivation of X chromosome in females that influence in a sex-dependent manner onset, progression, and response to therapy of different diseases like cancer. There is evidence of a correlation between miRNAs, sex, and cancer both in solid tumors and in hematological malignancies; as an example, in lymphomas, with a prevalence rate higher in men than women, miR-142 is "silenced" because of its hypermethylation by DNA methyltransferase-1 and it is blocked in its normal activity of regulating the migration of the cell. This condition corresponds in clinical practice with a more aggressive tumor. In addition, cancer treatment can have advantages from the evaluation of miRNAs expression; in fact, therapy with estrogens in hepatocellular carcinoma determines an upregulation of the oncosuppressors miR-26a, miR-92, and miR-122 and, consequently, apoptosis. The aim of this review is to present an exhaustive collection of scientific data about the possible role of sex differences on the expression of miRNAs and the mechanisms through which miRNAs influence cancerogenesis, autophagy, and apoptosis of cells from diverse types of tumors.
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Affiliation(s)
- Santino Caserta
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (S.C.); (A.A.)
| | - Sebastiano Gangemi
- Allergy and Clinical Immunology Unit, Department of Clinical and Experimental Medicine, University of Messina, Via Consolare Valeria, 98125 Messina, Italy;
| | - Giuseppe Murdaca
- Department of Internal Medicine, University of Genova, Viale Benedetto XV, 16132 Genova, Italy
- IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy
| | - Alessandro Allegra
- Division of Hematology, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (S.C.); (A.A.)
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Meng X, Liu X. Therapeutic Value of Estrogen Receptor α in Hepatocellular Carcinoma Based on Molecular Mechanisms. J Clin Transl Hepatol 2022; 10:140-146. [PMID: 35233383 PMCID: PMC8845150 DOI: 10.14218/jcth.2021.00224] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/07/2021] [Accepted: 07/12/2021] [Indexed: 12/04/2022] Open
Abstract
The incidence of hepatocellular carcinoma (HCC) is significantly lower in women than men, implying that estrogen receptors (ERs) may play an important role in this sex dimorphism. Recently, considerable progress has been made in expanding our understanding of the mechanisms of ERs in HCC. As one of the most important ERs, ERα functions as a tumor suppressor in the progression of HCC through various pathways, such as STAT3 signaling pathways, lipid metabolism-related signaling pathways, and non-coding RNAs. However, the function of ERα was reduced with the changes of some molecules in the liver, which may develop further into HCC and make it difficult to achieve an effective hormone treatment effect. Intriguingly, there are signs that individualized hormone therapy according to the activity of ERα will overcome this challenge. Based on these observations, it is particularly imperative to reassess and extend the function of ERα. In this review, we mainly elucidated molecular mechanisms associated with ERα in HCC and investigated the individualized hormone therapy based on these mechanisms, with the aim of providing new insights for HCC treatment.
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Affiliation(s)
- Xiangzhe Meng
- Second Clinical College, Jining Medical University, Jining, Shandong, China
| | - Xue Liu
- Department of Pathology, College of Basic Medicine, Jining Medical University, Jining, Shandong, China
- Correspondence to: Xue Liu, Department of Pathology, College of Basic Medicine, Jining Medical University, 133 Hehua Road, Jining, Shandong 272067, China. ORCID: https://orcid.org/0000-0001-7817-8392. Tel: +86-15053798589, E-mail:
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10
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Elghoroury EA, Abdelghaffar EE, Awadallah E, Kamel SA, Kandil D, Hassan EM, Hassan M, Kamel MM, Gomaa MM, Fathalla LA. Detection of exosomal miR-18a and miR-222 levels in Egyptian patients with hepatic cirrhosis and hepatocellular carcinoma. Int J Immunopathol Pharmacol 2022; 36:3946320221097832. [PMID: 35467432 PMCID: PMC9047801 DOI: 10.1177/03946320221097832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is known to be the second leading cause of cancer-related mortality worldwide. For improving the prognosis as well as reducing the rate of mortality, early diagnosis of HCC is a must. AIMS This study was conducted to assess the ability of the serum expression of exosomal miR-18a and miR-222 to differentiate and diagnose patients with HCC, patients with liver cirrhosis, and healthy controls. METHODS This study included 51 patients with liver cirrhosis, 51 patients with HCC on top of hepatitis C virus (HCV) infection, and 50 healthy controls. RESULTS miR-18a and miR-222 were assessed using reverse transcription-polymerase chain reaction. MiR-18a and miR-222 levels were significantly higher in the liver cirrhosis and HCC groups than the control group (p ˂ 0.001). However, no statistically significant difference was found between patients with HCC and liver cirrhosis (p = 0.4 for miR-18a and p = 0.1 for miR-222). ROC curve analyses to evaluate the diagnostic performances of the two miRNAs as important noninvasive diagnostic markers revealed a best cutoff value of 2 for miR-18a to differentiate between liver cirrhosis, HCC, and healthy controls. And for mir-222, a cutoff value of 1.7 and 1.9 showed the highest specificity for discrimination between liver cirrhosis, HCC, and healthy controls, respectively. Moreover, logistic regression model revealed that miR-18a expression was independent predictive factor in HCC patients (p = 0.004), while miR-222 expression was independent predictive factor in liver cirrhosis patients (p < 0.001). CONCLUSION miR-18a and miR-222 were significantly discriminative markers between patients with liver cirrhosis and HCC and healthy individuals. Therefore, they have a prognostic rather than a diagnostic value. Moreover, miR-18a and miR-222 could be useful in identifying liver injuries, including fibrosis and cirrhosis.
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Affiliation(s)
- Eman A Elghoroury
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Esmat E Abdelghaffar
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Eman Awadallah
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Solaf A Kamel
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Dina Kandil
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Eman M Hassan
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Mirhane Hassan
- Clinical and Chemical Pathology Department, 68787National Research Centre, Dokki, Cairo, Egypt
| | - Mahmoud M Kamel
- Clinical and Chemical Pathology Department, 68804National Cancer Institute, Cairo University, Cairo, Egypt
| | - Mohammed M Gomaa
- Department of Diagnostic and Interventional Radiology, 68804National Cancer Institute, Cairo University, Cairo, Egypt
| | - Lamiaa A Fathalla
- Clinical and Chemical Pathology Department, 68804National Cancer Institute, Cairo University, Cairo, Egypt
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Chen P, Li B, Ou-Yang L. Role of estrogen receptors in health and disease. Front Endocrinol (Lausanne) 2022; 13:839005. [PMID: 36060947 PMCID: PMC9433670 DOI: 10.3389/fendo.2022.839005] [Citation(s) in RCA: 88] [Impact Index Per Article: 29.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 07/26/2022] [Indexed: 12/14/2022] Open
Abstract
Estrogen receptors (ERs) regulate multiple complex physiological processes in humans. Abnormal ER signaling may result in various disorders, including reproductive system-related disorders (endometriosis, and breast, ovarian, and prostate cancer), bone-related abnormalities, lung cancer, cardiovascular disease, gastrointestinal disease, urogenital tract disease, neurodegenerative disorders, and cutaneous melanoma. ER alpha (ERα), ER beta (ERβ), and novel G-protein-coupled estrogen receptor 1 (GPER1) have been identified as the most prominent ERs. This review provides an overview of ERα, ERβ, and GPER1, as well as their functions in health and disease. Furthermore, the potential clinical applications and challenges are discussed.
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Affiliation(s)
| | - Bo Li
- *Correspondence: Bo Li, libo‐‐
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12
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Wu J, Nagy LE, Liangpunsakul S, Wang L. Non-coding RNA crosstalk with nuclear receptors in liver disease. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166083. [PMID: 33497819 PMCID: PMC7987766 DOI: 10.1016/j.bbadis.2021.166083] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/28/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023]
Abstract
The dysregulation of nuclear receptors (NRs) underlies the pathogenesis of a variety of liver disorders. Non-coding RNAs (ncRNAs) are defined as RNA molecules transcribed from DNA but not translated into proteins. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two types of ncRNAs that have been extensively studied for regulating gene expression during diverse cellular processes. NRs as therapeutic targets in liver disease have been exemplified by the successful application of their pharmacological ligands in clinics. MiRNA-based reagents or drugs are emerging as flagship products in clinical trials. Advancing our understanding of the crosstalk between NRs and ncRNAs is critical to the development of diagnostic and therapeutic strategies. This review summarizes recent findings on the reciprocal regulation between NRs and ncRNAs (mainly on miRNAs and lncRNAs) and their implication in liver pathophysiology, which might be informative to the translational medicine of targeting NRs and ncRNAs in liver disease.
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Affiliation(s)
- Jianguo Wu
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America.
| | - Laura E Nagy
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Gastroenterology and Hepatology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States of America; Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, United States of America
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States of America; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States of America
| | - Li Wang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, United States of America
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13
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Guo Y, Wu G, Yi J, Yang Q, Jiang W, Lin S, Yang X, Cai X, Mao L. Anti-Hepatocellular Carcinoma Effect and Molecular Mechanism of the Estrogen Signaling Pathway. Front Oncol 2021; 11:763539. [PMID: 35096574 PMCID: PMC8789654 DOI: 10.3389/fonc.2021.763539] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 12/14/2021] [Indexed: 12/18/2022] Open
Abstract
There are significant gender differences in the incidence and mortality of hepatocellular carcinoma (HCC). Compared with men, the incidence and mortality of HCC in women are relatively low. The estrogen signaling pathway, composed of estrogen and estrogen receptors, has been postulated to have a protective effect on the occurrence and development of HCC. There have been multiple studies that have supported anti-HCC effects of the estrogen signaling pathways, including direct and indirect pathways such as genomic pathways, rapid transduction pathways, non-coding RNA, tumor microenvironment, estrogen metabolites, and inhibition of hepatitis infection and replication. Based on the evidence of an anti-HCC effect of the estrogen signaling pathway, a number of strategies have been investigated to determine the potential therapeutic effect. These have included estrogen replacement therapy, targeting the estrogen receptor, key molecules, inflammatory mediators, and regulatory pathways of the estrogen signaling pathway. In this review, we have systematically summarized the latest developments in the complex functions and molecular mechanisms of the estrogen signaling pathway in liver cancer. Furthermore, we have highlighted the potential targets of treatment strategies based on the estrogen signaling pathway in the treatment of liver cancer and the principal obstacles currently encountered for future investigation.
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Affiliation(s)
- Yusheng Guo
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Guohui Wu
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Junrong Yi
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Qin Yang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wengong Jiang
- Nephrology Department, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Shaoqiang Lin
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Xiaorong Yang
- Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Xiangsheng Cai
- Center for Medical Experiments, University of Chinese Academy of Science-Shenzhen Hospital, Shenzhen, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
| | - Liufeng Mao
- Scientific Research Center, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- *Correspondence: Liufeng Mao, ; Xiangsheng Cai, ; Xiaorong Yang,
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14
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Cao H, Chen X, Wang Z, Wang L, Xia Q, Zhang W. The role of MDM2-p53 axis dysfunction in the hepatocellular carcinoma transformation. Cell Death Discov 2020; 6:53. [PMID: 32595984 PMCID: PMC7305227 DOI: 10.1038/s41420-020-0287-y] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 05/24/2020] [Accepted: 05/28/2020] [Indexed: 12/12/2022] Open
Abstract
Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4+T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.
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Affiliation(s)
- Hui Cao
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Xiaosong Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Zhijun Wang
- Department of Traditional Chinese Medicine, Putuo People’s Hospital Affiliated to Tongji University, Shanghai, China
| | - Lei Wang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127 China
| | - Wei Zhang
- Department of Liver Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030 China
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Li Y, Xu A, Jia S, Huang J. Recent advances in the molecular mechanism of sex disparity in hepatocellular carcinoma. Oncol Lett 2019; 17:4222-4228. [PMID: 30988804 PMCID: PMC6447942 DOI: 10.3892/ol.2019.10127] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 01/25/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is more frequently observed and aggressive in men compared with women. Increasing evidence demonstrates that the sex disparity appears to be mediated by the stimulatory effects of androgens and the protective effects of estrogen in the development and progression of HCC. In the past few decades, studies on the sex difference of HCC mainly focused on the effect of sex hormones on the transactivation of hepatitis B virus X protein and the release of inflammatory cytokines, and these studies have further intensified in recent years. Sex hormones are also involved in genetic alterations and DNA damage repair in hepatocytes through binding to their specific cellular receptors and affecting the corresponding signaling pathways. Furthermore, the theory of sex chromosomes participating in HCC has been considered. The present review discussed the recent advances in the molecular mechanisms of sex disparity in HCC, with the aim of improving the understanding of the underlying critical factors and exploring more effective methods for the prevention and treatment of HCC.
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Affiliation(s)
- Yanmeng Li
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Anjian Xu
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Siyu Jia
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
| | - Jian Huang
- Experimental Center, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China
- National Clinical Research Center for Digestive Disease, Beijing 100050, P.R. China
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16
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Li CL, Li CY, Lin YY, Ho MC, Chen DS, Chen PJ, Yeh SH. Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region. Hepatology 2019; 69:498-512. [PMID: 30070724 DOI: 10.1002/hep.30201] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 07/31/2018] [Indexed: 12/15/2022]
Abstract
The gender disparity of hepatocellular carcinoma (HCC) is most striking in hepatitis B virus (HBV)-related cases. The majority of such HCC cases contain integrated HBV, and some hotspot integrations, such as those in the telomerase reverse transcriptase gene (TERT) promoter, activate gene expression to drive carcinogenesis. As the HBV genome contains both androgen-responsive and estrogen-responsive motifs, we hypothesized that the integrated HBV DNA renders a similar regulation for downstream gene expression and thus contributes to male susceptibility to HCC. To test this hypothesis, the HBV integration sites and the common mutations in the TERT promoter and tumor protein P53 (TP53) coding region were analyzed in 101 HBV-related HCC cases using a capture-next-generation sequencing platform. The results showed that both HBV integration and -124G>A mutation in the TERT promoter region, occurring in a mutually exclusive manner, were more frequent in male than in female patients with HCC (integration: 22/58 male patients with HCC, 6/36 female patients with HCC, P = 0.0285; -124G>A: 17/62 male patients with HCC, 3/39 female patients with HCC, P = 0.0201; in combination, 39/62 male patients with HCC, 9/39 female patients with HCC, P < 0.0001). The effects of sex hormone pathways on the expression of TERT with both genetic changes were investigated using a reporter assay. HBV integration in the TERT promoter rendered the TERT transcription responsive to sex hormones, with enhancement by androgen receptor (AR) but suppression by estrogen receptor, both of which were dependent on hepatocyte nuclear factor 4 alpha. Besides, AR also increased TERT expression by targeting TERT promoter mutations in a GA binding protein transcription factor subunit alpha-dependent manner. Conclusion: TERT elevation by AR through integrated HBV and point mutation at the TERT promoter region was identified as a mechanism for the male dominance of HBV-related HCCs; telomerase and AR thus may be targets for intervention of HCC.
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Affiliation(s)
- Chiao-Ling Li
- Department of Microbiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Chen-Yu Li
- Department of Microbiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - You-Yu Lin
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Ming-Chih Ho
- Department of Surgery, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Ding-Shinn Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,National Taiwan University Center for Genomic Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan.,Department of Laboratory Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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17
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Sanchez-Mejias A, Kwon J, Chew XH, Siemens A, Sohn HS, Jing G, Zhang B, Yang H, Tay Y. A novel SOCS5/miR-18/miR-25 axis promotes tumorigenesis in liver cancer. Int J Cancer 2018; 144:311-321. [DOI: 10.1002/ijc.31857] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 07/14/2018] [Accepted: 08/15/2018] [Indexed: 12/11/2022]
Affiliation(s)
- Avencia Sanchez-Mejias
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Junsu Kwon
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Xiao Hong Chew
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Angela Siemens
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Hye Seon Sohn
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Guo Jing
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Bin Zhang
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
| | - Yvonne Tay
- Cancer Science Institute of Singapore, Centre for Translational Medicine; National University of Singapore; Singapore 117599 Singapore
- Department of Biochemistry; Yong Loo Lin School of Medicine, National University of Singapore; Singapore 117597 Singapore
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18
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Zhou J, Wang M, Deng D. c-Fos/microRNA-18a feedback loop modulates the tumor growth via HMBOX1 in human gliomas. Biomed Pharmacother 2018; 107:1705-1711. [PMID: 30257388 DOI: 10.1016/j.biopha.2018.08.157] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 08/31/2018] [Accepted: 08/31/2018] [Indexed: 12/11/2022] Open
Abstract
Glioma is one of the most aggressive and lethal human cancers in central nervous system (CNS). Recent studies have identified many dysregulated microRNAs (miRNA, miR) in human glioma, which are a class of small non-coding RNA molecules. Increasing data have shown that miR-18a plays significant roles in several tumors. However, its effects on glioma are unclear. In this study, we found the elevated expression of c-Fos and miR-18a in tissues of human glioma patients and glioma cells. Then the miR-18a inhibitor or c-Fos siRNA were transfected into glioma cells line H4 to determine their effects on H4 cells. MTT assay showed that both miR-18a inhibitor and si-c-Fos suppressed the H4 cell proliferation. Transwell assay showed the reduced cell migration by miR-18a inhibitor and si-c-Fos in H4 cells. The increased level of H4 cells apoptosis by miR-18a inhibitor and si-c-Fos was also determined. Moreover, knockout of c-Fos decreased the miR-18a level, while miR-18a inhibitor reduced the c-Fos level in H4 cells. Added with the results of ChIP assay, this report showed a positive feedback between c-Fos and miR-18a. Finally, luciferase assay showed that HMBOX1 was directly targeted by miR-18a in H4 cells, and the HMBOX1 siRNA reversed the effects of miR-18a inhibitor on cell proliferation, migration and apoptosis of H4 cells. In conclusion, our study determine that c-Fos/miR-18a feedback loop promotes the tumor growth of gliomas by HMBOX1, providing important clues for understanding the key roles of transcription factor mediated mRNA-miRNA functional network in the regulation of gliomas.
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Affiliation(s)
- Jingbin Zhou
- Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, Liaoning, PR China
| | - Muchun Wang
- Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, Liaoning, PR China
| | - Dongfeng Deng
- Department of Neurosurgery, Affiliated Zhongshan Hospital of Dalian University, Dalian, 116001, Liaoning, PR China.
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Peng W, Liu YN, Zhu SQ, Li WQ, Guo FC. The correlation of circulating pro-angiogenic miRNAs' expressions with disease risk, clinicopathological features, and survival profiles in gastric cancer. Cancer Med 2018; 7:3773-3791. [PMID: 30003708 PMCID: PMC6089172 DOI: 10.1002/cam4.1618] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 05/17/2018] [Accepted: 05/25/2018] [Indexed: 12/27/2022] Open
Abstract
This study aimed to explore the correlation of circulating pro‐angiogenic miRNAs’ expressions with risk, clinicopathological features, and survival profiles in gastric cancer (GC). Three hundred and thirty‐three GC patients underwent radical resection and 117 health controls (HCs) were recruited for this study. Plasma samples were obtained from GC patients before the operation and from HCs after enrollment. Fourteen pro‐angiogenic miRNAs were asseassed by quantitative polymerase chain reaction (qPCR). Disease‐free survival (DFS) and overall survival (OS) of GC patients were calculated and the median follow‐up duration was 36.0 months. Seven out of 14 pro‐angiogenic miRNAs including let‐7f, miR‐17‐5p, miR‐18a, miR‐19b‐1, miR‐20a, miR‐210, and miR‐296 were observed to be elevated in GC patients compared with HCs. MiR‐18a, miR‐20a, and miR‐210 disclosed good predictive values of GC risk. Six pro‐angiogenic miRNAs including miR‐17‐5p, miR‐92a, miR‐210, miR‐20a, miR‐18a, and miR‐296 expressions were positively while 1 pro‐angiogenic miRNA (miR‐130a) was negatively correlated with tumor malignancy degree in GC patients. K‐M curve disclosed that 5 pro‐angiogenic miRNAs including miR‐17‐5p, miR‐18a, miR‐20a, miR‐92a, and miR‐210 correlated with worse DFS, while 4 pro‐angiogenic miRNAs including miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 associated with shorter OS. Further multivariate Cox's analysis revealed that miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 were independent predictive factors for unfavorable DFS and OS. In conclusion, circulating pro‐angiogenic miRNAs could serve as novel noninvasive biomarkers for disease risk and malignancy degree, and miR‐17‐5p, miR‐18a, miR‐20a, and miR‐210 are independent factors predicting poor prognosis in GC patients.
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Affiliation(s)
- Wei Peng
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Ya-Nan Liu
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Si-Qiang Zhu
- Deparment of General Surgery, No. 211 Hospital of PLA, Harbin, China
| | - Wen-Qiang Li
- Department of General Surgery, Guangdong General Hospital Zhuhai Hospital (Zhuhai Golden Bay Center Hospital), Zhuhai, China
| | - Feng-Cheng Guo
- Deparment of General Surgery, No. 211 Hospital of PLA, Harbin, China
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Werneck AO, Coelho-E-Silva MJ, Padilha CS, Ronque ERV, Cyrino ES, Szwarcwald CL, Silva DR. Age at menarche and cancer risk at adulthood. Ann Hum Biol 2018; 45:369-372. [PMID: 29807473 DOI: 10.1080/03014460.2018.1470670] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
AIM The aim was to evaluate the association between age at menarche and cancer using a nationally representative sample of Brazilian women. METHODS Data from the Brazilian Health Survey (PNS), a nationally representative survey conducted in 2013 (n = 33,715 women; ≥18 years), were used. Information on cancer diagnosis, age at menarche and other co-variables (chronological age, educational status, skin colour, menopause, leisure-time physical activity and tobacco smoking) were collected via interview. Logistic regression models were used for aetiological analyses. RESULTS The prevalence of cancer diagnosis was greater among women with early age at menarche [2.6% (2.0-3.5%)] compared to on-time [1.6% (1.4-1.9%)] and late women [2.0% (1.1-3.4%)]. The onset of menarche ≤11 years was significantly associated with cancer risk, regardless of co-variables [OR =2.45 (1.34-4.48)], compared to the late group. CONCLUSION Early age at menarche was associated with cancer risk in adulthood, regardless of race, educational status, chronological age, obesity, menopause onset, tobacco smoking or physical activity.
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Affiliation(s)
- André O Werneck
- a Study and Research Group in Metabolism, Nutrition, and Exercise - GEPEMENE , State University of Londrina - UEL , Londrina , Brazil
| | - Manuel J Coelho-E-Silva
- b Faculty of Sports Sciences and Physical Education, University of Coimbra , Coimbra , Portugal
| | - Camila S Padilha
- a Study and Research Group in Metabolism, Nutrition, and Exercise - GEPEMENE , State University of Londrina - UEL , Londrina , Brazil
| | - Enio R V Ronque
- a Study and Research Group in Metabolism, Nutrition, and Exercise - GEPEMENE , State University of Londrina - UEL , Londrina , Brazil
| | - Edilson S Cyrino
- a Study and Research Group in Metabolism, Nutrition, and Exercise - GEPEMENE , State University of Londrina - UEL , Londrina , Brazil
| | - Célia L Szwarcwald
- c Fundação Oswaldo Cruz (Fiocruz), Instituto de Comunicação e Informação Científica e Tecnológica em Saúde , Rio de Janeiro , Brazil
| | - Danilo R Silva
- d Department of Physical Education , Federal University of Sergipe - UFS , São Cristóvão , Brazil
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21
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Ye Y, Wang G, Wang G, Zhuang J, He S, Song Y, Ni J, Xia W, Wang J. The Oncogenic Role of Tribbles 1 in Hepatocellular Carcinoma Is Mediated by a Feedback Loop Involving microRNA-23a and p53. Front Physiol 2017; 8:789. [PMID: 29176948 PMCID: PMC5686088 DOI: 10.3389/fphys.2017.00789] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 09/26/2017] [Indexed: 01/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common malignancy associated with a high risk of recurrence and metastasis and a poor prognosis. Here, we examined the involvement of the pseudokinase Tribbles 1 (TRIB1), a scaffold protein associated with several malignancies, in HCC and investigated the underlying mechanisms. TRIB1 was upregulated in HCC tissues and cell lines in correlation with low levels of p53. TRIB1 gain and loss of function experiments indicated that TRIB1 promoted HCC cell viability concomitant with the downregulation of p53, and induced HCC cell migration, invasion, and epithelial-mesenchymal transition. TRIB1 was identified as a target of microRNA-23a (miR-23a), and miR-23a overexpression downregulated TRIB1 and upregulated p53 in HCC cells. Ectopic expression of TRIB1 upregulated β-catenin and its effectors c-myc and MMP-7 in a p53-dependent manner. TRIB1 silencing inhibited tumor growth and promoted apoptosis in vivo via a mechanism that would involve the modulation of p53 and β-catenin signaling. The present results indicate that TRIB1 promotes HCC tumorigenesis and invasiveness via a feedback loop that involves the modulation of its expression by miR-23a with the likely downregulation of p53, and suggest the involvement of the β-catenin signaling pathway. These findings suggest potential targets for the treatment of HCC and therefore merit further investigation.
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Affiliation(s)
- Ying Ye
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guangdong Wang
- Department of Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guoyu Wang
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Juhua Zhuang
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Saifei He
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanan Song
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Ni
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei Xia
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiening Wang
- Department of Nuclear Medicine, The Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
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22
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Liu L, Cai X, Liu E, Tian X, Tian C. MicroRNA-18a promotes proliferation and metastasis in hepatocellular carcinoma via targeting KLF4. Oncotarget 2017; 8:68263-68269. [PMID: 28978114 PMCID: PMC5620254 DOI: 10.18632/oncotarget.19293] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Accepted: 06/19/2017] [Indexed: 01/02/2023] Open
Abstract
MicroRNAs (miRNAs) are short, non-coding and endogenous RNAs that played as important roles in the proliferation and metastasis of tumors. In this study, we determined the role of miR-18a in the regulation of HCC cell motility. We showed that miR-18a expression was upregulated in human HCC tissues and cell lines. Moreover, Elevated expression of miR-18a promoted the HCC cell proliferation and migration. KLF4 was identified as a direct target of miR-18a in HCC cells. Furthermore, overexpression of KLF4 attenuated the effects of miR-18a on the regulation of HCC cell motility. The expression of KLF4 was negatively associated with the expression of miR-18a expression in HCC tissues. We also showed that the cell cycle inhibitor p21 was aberrantly downregulated in HCC cells, whereas this inhibition was reversed by miR-18a inhibitor. These data indicated that miR-18a may play a positive role in hepatocellular carcinoma by promoting the proliferation and migration of HCC cells through targeting KLF4 as well as downstream p21.
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Affiliation(s)
- Li Liu
- Department of Medicine & Appliance, Yunyan District Market Supervision and Administration Bureau, Guizhou 550001, China
| | - Xun Cai
- Department of Oncology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200080, China
| | - Enqiang Liu
- Department of Oncology, Qianjiang Central Hospital of Chongqing Municipality, Chongqing 409000, China
| | - Xia Tian
- Department of Nuclear Medicine, Guizhou Provincial People’s Hospital, Guizhou 550000, China
| | - Chuan Tian
- Department of Nuclear Medicine, Guizhou Provincial People’s Hospital, Guizhou 550000, China
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MicroRNAs as Key Effectors in the p53 Network. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2017; 333:51-90. [PMID: 28729028 DOI: 10.1016/bs.ircmb.2017.04.003] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The guardian of the genome p53 is embedded in a fine-spun network of MicroRNAs. p53 is able to activate or repress directly the transcription of MicroRNAs that are participating in the tumor-suppressive mission of p53. On the other hand, the expression of p53 is under tight control of MicroRNAs that are either targeting directly p53 or factors that are modifying its protein level or activity. Although the most important function of p53 is suggested to be transcriptional regulation, there are several nontranscriptional functions described. One of those regards the modulation of MicroRNA biogenesis. Wild-type p53 is increasing the maturation of selected MicroRNAs from the primary transcript to the precursor MiRNA by interacting with the Microprocessor complex. Furthermore, p53 is modulating the mRNA accessibility for certain MicroRNAs by association with the RISC complex and transcriptional regulation of RNA-binding proteins. In this way p53 is able to remodel the MiRNA-mRNA interaction network. As wild-type p53 is employing MicroRNAs to suppress cancer development, gain-of-function mutant p53 proteins use MicroRNAs to confer oncogenic properties like chemoresistance and the ability to drive metastasis. Like its wild-type counterpart mutant p53 is able to regulate MicroRNAs transcriptionally and posttranscriptionally. Mutant p53 affects the MiRNA processing at two cleavage steps through interfering with the Microprocessor complex and by downregulating Dicer and KSRP, a modulator of MiRNA biogenesis. Thus, MicroRNAs are essential components in the p53 pathway, contributing substantially to combat or enhance tumor development depending on the wild-type or mutant p53 context.
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MicroRNA-18a-5p functions as an oncogene by directly targeting IRF2 in lung cancer. Cell Death Dis 2017; 8:e2764. [PMID: 28471447 PMCID: PMC5520692 DOI: 10.1038/cddis.2017.145] [Citation(s) in RCA: 98] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 03/01/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023]
Abstract
Lung cancer is the major form of cancer resulting in cancer-related mortality around the world. MicroRNAs are endogenous small non-coding single-stranded RNAs, which can engage in the regulation of gene expression. In this study, miR-18a-5p significantly upregulated in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines, suggesting an oncogenic function in lung cancer. Additionally, miR-18a-5p can promote carcinogenesis by directly targeting interferon regulatory factor 2 (IRF2). Further experiments indicated that IRF2 can increase cell apoptosis, inhibit cell proliferation and migration ability. Our study demonstrates that miR-18a-5p promotes autophagy in NSCLC. Collectively, these results indicate that miR-18a-5p can not only promote NSCLC by suppressing IRF2, but also will be a promising target in the near future.
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Kwekel JC, Vijay V, Han T, Moland CL, Desai VG, Fuscoe JC. Sex and age differences in the expression of liver microRNAs during the life span of F344 rats. Biol Sex Differ 2017; 8:6. [PMID: 28174625 PMCID: PMC5291947 DOI: 10.1186/s13293-017-0127-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/27/2017] [Indexed: 12/19/2022] Open
Abstract
Background Physiological factors such as age and sex have been shown to be risk factors for adverse effects in the liver, including liver diseases and drug-induced liver injury. Previously, we have reported age- and sex-related significant differences in hepatic basal gene expression in rats during the life span that may be related to susceptibility to such adverse effects. However, the underlying mechanisms of the gene expression changes were not fully understood. In recent years, increasing evidence for epigenetic mechanisms of gene regulation has fueled interest in the role of microRNAs (miRNAs) in toxicogenomics and biomarker discovery. We therefore proposed that significant age and sex differences exist in baseline liver miRNA expression, and that comprehensive profiling of miRNAs will provide insights into the epigenetic regulation of gene expression in rat liver. Methods To address this, liver tissues from male and female F344 rats were examined at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age for the expression of 677 unique miRNAs. Following data processing, predictive pathway analysis was performed on selected miRNAs that exhibited prominent age and/or sex differences in expression. Results Of the 314 miRNAs found to be expressed, 214 were differentially expressed; 65 and 212 miRNAs showed significant (false discovery rate (FDR) <5% and ≥1.5-fold change) sex- and age-related differences in expression, respectively. Thirty-eight miRNAs showed 2-week-specific expression, of which 31 miRNAs were found to be encoded within the Dlk1-Dio3 cluster located on chromosome 6. This cluster has been associated with tissue proliferation and differentiation, and liver energy homeostasis in postnatal development. Predictive pathway analysis linked sex-biased miRNA expression with sexually dimorphic molecular functions and toxicological functions that may reflect sex differences in hepatic physiology and disease. The expression of miRNAs (miR-18a, miR-99a, and miR-203, miR-451) was also found to associate with specific sexually dimorphic hepatic histopathology. The expression of miRNAs involved in regulating cell death, cell proliferation, and cell cycle was found to change as the rats matured from adult to old age. Conclusions Overall, significant age- and sex-related differences in liver miRNA expression were identified and linked to histopathological findings and predicted functional pathways that may underlie susceptibilities to liver toxicity and disease. Electronic supplementary material The online version of this article (doi:10.1186/s13293-017-0127-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Joshua C Kwekel
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA.,Present address: Department of Math & Science, Central Baptist College, Conway, AR USA
| | - Vikrant Vijay
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA
| | - Tao Han
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA
| | - Carrie L Moland
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA
| | - Varsha G Desai
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA
| | - James C Fuscoe
- Division of Systems Biology, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR USA
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Pollutri D, Gramantieri L, Bolondi L, Fornari F. TP53/MicroRNA Interplay in Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:ijms17122029. [PMID: 27918441 PMCID: PMC5187829 DOI: 10.3390/ijms17122029] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 11/23/2016] [Accepted: 11/28/2016] [Indexed: 02/07/2023] Open
Abstract
The role of microRNAs as oncogenes and tumor suppressor genes has emerged in several cancers, including hepatocellular carcinoma (HCC). The pivotal tumor suppressive role of p53-axis is indicated by the presence of inactivating mutations in TP53 gene in nearly all cancers. A close interaction between these two players, as well as the establishment of complex p53/miRNAs loops demonstrated the strong contribution of p53-effector miRNAs in enhancing the p53-mediated tumor suppression program. On the other hand, the direct and indirect targeting of p53, as well as the regulation of its stability and activity by specific microRNAs, underlie the importance of the fine-tuning of p53 pathway, affecting the cell fate of damaged/transformed cells. The promising results of miRNAs-based therapeutic approaches in preclinical studies and their entrance in clinical trials demonstrate the feasibility of this strategy in several diseases, including cancer. Molecularly targeted drugs approved so far for HCC treatment show intrinsic or acquired resistances with disease progression in many cases, therefore the identification of effective and non-toxic agents for the treatment of HCC is actually an unmet clinical need. The knowledge of p53/miRNA inter-relations in HCC may provide useful elements for the identification of novel combined approaches in the context of the “personalized-medicine” era.
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Affiliation(s)
- Daniela Pollutri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Laura Gramantieri
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
| | - Luigi Bolondi
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy.
| | - Francesca Fornari
- Center for Applied Biomedical Research, St. Orsola-Malpighi University Hospital, 40138 Bologna, Italy.
- Department of Medical and Surgical Sciences, Bologna University, 40138 Bologna, Italy.
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Alternative splicing of estrogen receptor alpha in hepatocellular carcinoma. BMC Cancer 2016; 16:926. [PMID: 27899088 PMCID: PMC5129602 DOI: 10.1186/s12885-016-2928-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2015] [Accepted: 11/06/2016] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND The role of estrogen receptor alpha (ERa), estrogen receptor beta (ERb) and ERa36 signaling in hepatocellular carcinoma (HCC) is not fully addressed. METHODS In this study, three cohorts were included: (i) primary HCC patients (N = 76, cohort P), (ii) colorectal liver metastasis (mCRC) (N = 32, cohort S), and (iii) HCC from The Cancer Genome Atlas (TCGA) (N = 121). The levels of ERa36 and wtER36 were measured and their correlation with clinicopathologic features was determined. RESULTS WtERa was downregulated and that ERa36 was upregulated in tumor tissues in both cohort P and TCGA data set. ERa36 was downregulated in tumor tissues in cohort S. In cohort P, wtERa was differentially expressed in gender (P < 0.000), age (P = 0.004), tumor number (P = 0.043), tumor size (P = 0.002), intrahepatic recurrence (P = 0.054). ERa36 was unequally expressed in different non-tumor liver status (P = 0.040). WtERa was negatively associated with overall survival (OS) and disease free survival (DFS) in cohort P. Compared with non-tumor tissues, the expression of ERa36 was increased in primary HCC but decreased in secondary HCC, showing opposite expression patterns of ERa36 between primary HCC and secondary HCC. CONCLUSIONS Primary HCC is associated with the decreased WtERa but increased ERa36. The expression pattern of ERa36 is different between primary HCC and secondary HCC, as the former with the increased ERa36 but the latter with the decreased ERa36. Therefore, the expression of ERa36 may be used to differentiate the primary HCC and the secondary one.
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Zhong GC, Liu Y, Chen N, Hao FB, Wang K, Cheng JH, Gong JP, Ding X. Reproductive factors, menopausal hormone therapies and primary liver cancer risk: a systematic review and dose-response meta-analysis of observational studies. Hum Reprod Update 2016; 23:126-138. [PMID: 27655589 DOI: 10.1093/humupd/dmw037] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 08/29/2016] [Accepted: 09/01/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A striking gender disparity in the incidence and outcome of primary liver cancer (PLC) has been well recognized. Mounting evidence from basic research suggests that hormonal factors may be involved in the gender disparity of PLC. Whether hormonal exposures in human subjects are associated with PLC risk is largely unknown. OBJECTIVE AND RATIONALE Whether reproductive factors and use of menopausal hormone therapies (MHTs) in women are associated with PLC risk remains controversial. We conducted this study to clarify this issue. SEARCH METHODS PubMed and EMBASE were searched to July, 2016 for studies published in English or Chinese. Observational studies (cohort, nested case-control and case-control) that provided risk estimates of reproductive factors, MHTs and PLC risk were eligible. The quality of included studies was determined based on the Newcastle-Ottawa quality assessment scale. Summary risk ratios (RRs) were calculated using a random-effects model. Dose-response analysis was conducted where possible. OUTCOMES Fifteen peer-reviewed studies, involving 1795 PLC cases and 2 256 686 women, were included. Overall meta-analyses on parity and PLC risk did not find any significant associations; however, when restricting to studies with PLC cases ≥100, increasing parity was found to be significantly associated with a decreased risk of PLC [RR for the highest versus lowest parity 0.67, 95% CI 0.52, 0.88; RR for parous versus nulliparous 0.71, 95% CI 0.53, 0.94; RR per one live birth increase 0.93, 95% CI 0.88, 0.99]. A J-shaped relationship between parity and PLC risk was identified (Pnon-linearity < 0.01). Compared with never users, the pooled RRs of PLC were 0.60 (95% CI 0.37, 0.96) for ever users of MHT, 0.73 (95% CI 0.46, 1.17) for ever users of estrogen-only therapy (ET) and 0.67 (95% CI 0.45, 1.02) for ever users of estrogen-progestin therapy (EPT). The pooled RR of PLC for the oldest versus youngest category of menarcheal age was 0.50 (95% CI 0.32, 0.79). Oophorectomy was significantly associated with an increased risk of PLC (RR 2.23, 95% CI 1.46, 3.41). No significant association of age at first birth, and spontaneous or induced abortion with PLC risk was found. No meta-analysis was performed for the association of age at menopause, breastfeeding, hysterectomy, menopausal status and stillbirth with PLC risk owing to huge methodological heterogeneity and/or very limited studies. WIDER IMPLICATIONS Parity is associated with PLC risk in a J-shaped dose-response pattern. Late age at menarche and ever use of MHT are associated with a reduced risk of PLC, whereas there is no association of ever use of ET and EPT, age at first birth, or spontaneous and induced abortion with PLC risk. Compared to women with no history of oophorectomy, those with a history of oophorectomy are at an increased risk of PLC. Our findings provide some epidemiological support for a role of hormonal exposures in the development of PLC in women. However, these findings should be interpreted with much caution because of the limited number of studies and potential biases, and need to be validated by studies with good design and large sample size.
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Affiliation(s)
- Guo-Chao Zhong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China
| | - Yan Liu
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China.,Department of Gastroenterology, The Fifth People's Hospital of Chengdu, 33 Mashi Street, Wenjiang District, Chengdu 611130, China
| | - Nan Chen
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China
| | - Fa-Bao Hao
- Department of Pediatric Surgery, Children's Hospital of Chongqing Medical University, 136 Zhongshan 2nd Road, Yuzhong District, Chongqing 400014, China
| | - Kang Wang
- Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, 1 Youyi Road, Yuanjiagang District, Chongqing 400016, China
| | - Jia-Hao Cheng
- Department of Urinary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China
| | - Jian-Ping Gong
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China
| | - Xiong Ding
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74 Linjiang Road, Yuzhong District, Chongqing 400010, China
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Gurtner A, Falcone E, Garibaldi F, Piaggio G. Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2016; 35:45. [PMID: 26971015 PMCID: PMC4789259 DOI: 10.1186/s13046-016-0319-x] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/03/2016] [Indexed: 12/13/2022]
Abstract
A widespread decrease of mature microRNAs is often observed in human malignancies giving them potential to act as tumor suppressors. Thus, microRNAs may be potential targets for cancer therapy. The global miRNA deregulation is often the result of defects in the miRNA biogenesis pathway, such as genomic mutation or aberrant expression/localization of enzymes and cofactors responsible of miRNA maturation. Alterations in the miRNA biogenesis machinery impact on the establishment and development of cancer programs. Accumulation of pri-microRNAs and corresponding depletion of mature microRNAs occurs in human cancers compared to normal tissues, strongly indicating an impairment of crucial steps in microRNA biogenesis. In agreement, inhibition of microRNA biogenesis, by depletion of Dicer1 and Drosha, tends to enhance tumorigenesis in vivo. The p53 tumor suppressor gene, TP53, is mutated in half of human tumors resulting in an oncogene with Gain-Of-Function activities. In this review we discuss recent studies that have underlined a role of mutant p53 (mutp53) on the global regulation of miRNA biogenesis in cancer. In particular we describe how a new transcriptionally independent function of mutant p53 in miRNA maturation, through a mechanism by which this oncogene is able to interfere with the Drosha processing machinery, generally inhibits miRNA processing in cancer and consequently impacts on carcinogenesis.
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Affiliation(s)
- Aymone Gurtner
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Emmanuela Falcone
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144, Rome, Italy
| | - Francesca Garibaldi
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144, Rome, Italy.
| | - Giulia Piaggio
- Department of Research, Advanced Diagnostics, and Technological Innovation, Regina Elena National Cancer Institute, 00144, Rome, Italy
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Xu P, Wu M, Chen H, Xu J, Wu M, Li M, Qian F, Xu J. Bioinformatics analysis of hepatitis C virus genotype 2a-induced human hepatocellular carcinoma in Huh7 cells. Onco Targets Ther 2016; 9:191-202. [PMID: 26811688 PMCID: PMC4712971 DOI: 10.2147/ott.s91748] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver cancer that could be induced by hepatitis C virus genotype 2a Japanese fulminant hepatitis-1 (JFH-1) strain. The aim of this study was to investigate the molecular mechanisms of HCC. The microarray data GSE20948 includes 14 JFH-1- and 14 mock (equal volume of medium [control])-infected Huh7 samples. The data were downloaded from the Gene Expression Omnibus. After data processing, soft cluster analyses were performed to identify co-regulated genes with similar temporal expression patterns. Functional and pathway enrichment analyses, as well as functional annotation analysis, were performed. Subsequently, combined networks of protein–protein interaction network, microRNA regulatory network, and transcriptional regulatory network were constructed. Hub nodes, modules, and five clusters of co-regulated genes were also identified. In total, 173 up and 207 down co-regulated genes were separately identified in JFH-1-infected Huh7 cells compared with those of control cells. Functional enrichment analysis indicated that up co-regulated genes were related to skeletal system morphogenesis and neuron differentiation and down co-regulated genes were related to steroid/cholesterol/sterol metabolisms. Hub genes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) were identified. Transcription factors IRF1 and Foxa1 were the targets of miR-130a, miR-17-5p, and miR-20a. PPARGC1A was targeted by miR-29 family, and MSMO1 was the target of miR-23 family. Hub nodes (such as IRF1, GBP1, ICAM1, Foxa1, DHCR7, HMGCS2, and MSMO1) and microRNAs might be used as candidate biomarkers of JFH-1-infected HCC.
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Affiliation(s)
- Ping Xu
- Inspection Center, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China; Key Laboratory of TB Prevention and Cure of Suzhou City, Suzhou, Jiangsu Province, People's Republic of China
| | - Meiying Wu
- Key Laboratory of TB Prevention and Cure of Suzhou City, Suzhou, Jiangsu Province, People's Republic of China; Department of Respiratory Medicine, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
| | - Hui Chen
- Inspection Center, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China; Key Laboratory of TB Prevention and Cure of Suzhou City, Suzhou, Jiangsu Province, People's Republic of China
| | - Junchi Xu
- Inspection Center, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China; Key Laboratory of TB Prevention and Cure of Suzhou City, Suzhou, Jiangsu Province, People's Republic of China
| | - Minjuan Wu
- Inspection Center, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
| | - Ming Li
- Department of Infectious Diseases, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
| | - Feng Qian
- Department of Infectious Diseases, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
| | - Junhua Xu
- Key Laboratory of TB Prevention and Cure of Suzhou City, Suzhou, Jiangsu Province, People's Republic of China; Department of Infectious Diseases, Affiliated Infectious Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
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Deng L, Yang H, Tang J, Lin Z, Yin A, Gao Y, Wang X, Jiang R, Sun B. Inhibition of MTA1 by ERα contributes to protection hepatocellular carcinoma from tumor proliferation and metastasis. J Exp Clin Cancer Res 2015; 34:128. [PMID: 26503703 PMCID: PMC4624357 DOI: 10.1186/s13046-015-0248-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Accepted: 10/19/2015] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Although expression of MTA1 inversely correlates with the nuclear localization of ERα, the effect and molecular mechanism of ERα regulation of MTA1 remain unknown. METHODS Quantitative real-time PCR and western blot analyses were used to measure levels of MTA1. The effect on HCC cell proliferation and invasion was assessed by EdU incorporation assays and Transwell, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between MTA1 and ERα in cell lines. RESULTS We found that MTA1 gene regulation by ERα may be influenced by nuclear corepressors. The MTA1 promoter has three functional ER-element half-sites that lead to decreased MTA1 transcription and expression. ERα overexpression suppressed the proliferation and invasion of hepatocellular carcinoma cells (HCC). In addition, overexpression of MTA1 attenuated ERα-mediated suppression of the proliferation and invasion of HCC cells and tumor formation in vivo. These results suggested feedback regulation between ERα and MTA1. In summary, our results demonstrated that ERα suppressed proliferation and invasion of human HCC cells through downregulation of MTA1 transcription. CONCLUSIONS Our study is an improved description of the mechanisms of the suppressive effect of ERα on HCCs, adding understanding to the gender disparity of HCC progression.
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Affiliation(s)
- Lei Deng
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Hui Yang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Junwei Tang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Zhe Lin
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Aihong Yin
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Yun Gao
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Xuehao Wang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China
| | - Runqiu Jiang
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, P.R. China.
| | - Beicheng Sun
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, P.R. China.
- Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, P.R. China.
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HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma. Crit Rev Oncol Hematol 2015; 97:312-21. [PMID: 26603462 DOI: 10.1016/j.critrevonc.2015.09.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 08/06/2015] [Accepted: 09/29/2015] [Indexed: 12/16/2022] Open
Abstract
The diagnosis and treatment of hepatocellular carcinoma (HCC) underwent a huge advancement in the last years. Recently, microRNAs (miRNAs) have been also studied to provide a new tool for early diagnosis of high risk patients, for prognostic classification to identify those patients who benefit cancer treatment and for predictive definition to select the right targeted drug. In this review we revised all the available data obtained to explore the role of miRNAs in HCC. This analysis led to identification of miRNAs which could gain a diagnostic, prognostic or predictive role. The results of studies on miRNAs involved in HCC are initial and far from providing scientific evidences to translate into clinical practice. We propose a classification of these miRNAs, that we could name HepatomiRNoma as a whole. Anyway prospective studies have to be designed to clarify the real clinical impact of this new tool.
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Lian JY, Tuo BG, Wen GR, Jin H, Liang T. Role of estrogen receptors in digestive system tumors. Shijie Huaren Xiaohua Zazhi 2015; 23:4227-4235. [DOI: 10.11569/wcjd.v23.i26.4227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Estrogen receptors are steroid hormone receptors that modulate the expression of target genes when bound to ligand. Humans have two ligand-activated transcription factors that bind to estrogen, encoded by separate genes, estrogen receptor α (ERα) and estrogen receptor β (ERβ). In addition, the membrane localized G protein-coupled estrogen receptor 1 (GPER1) can be activated by estradiol and mediate non-genomic signaling. Many studies have described the role of estrogen receptors in human cancers. Digestive system tumors account for a large proportion of all the tumors, and the mortality is very high in many digestive system tumors, such as esophageal cancer, gastric cancer, hepatocellular carcinoma, colorectal cancer, cholangiocarcinoma and pancreatic carcinoma. This review summarizes the role of estrogen receptors in digestive system tumors, aiming at finding new routes for the rational design of targeted anticancer therapies for digestive system tumors.
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34
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Wang SH, Chen PJ, Yeh SH. Gender disparity in chronic hepatitis B: Mechanisms of sex hormones. J Gastroenterol Hepatol 2015; 30:1237-45. [PMID: 25708186 DOI: 10.1111/jgh.12934] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/18/2015] [Indexed: 12/18/2022]
Abstract
Hepatitis B virus (HBV) is a common human pathogen transmitted worldwide, and its chronic infection is a well-known risk factor for hepatocellular carcinoma (HCC). The sex disparity of HBV-related liver diseases has been noticed for a long time, which could be attributed to sex hormone effects, other than gender behaviors or environmental impact. This difference is experimentally confirmed in HBV transgenic mice, as well as in immunocompetent mice receiving hydrodynamic delivery of HBV. Androgen and estrogen pathways were identified to play opposite regulations of HBV transcription by targeting viral enhancer I at molecular level. In addition to the direct effects on HBV life cycle, sex hormones may be also involved in the immune response to HBV infection and the progression of associated liver diseases, although the detailed mechanisms are still unclear. Besides, several unaddressed issues such as HBV entry, microRNA profiles, viral integration, and adaptability in which androgen and estrogen axes might be involved are warranted to be delineated. The comprehensive understanding of the sex disparity in HBV virology and pathogenesis will be helpful to provide newly biomarkers for clinical diagnosis and develop novel drugs to manage HBV-related HCC patients.
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Affiliation(s)
- Sheng-Han Wang
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Pei-Jer Chen
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
| | - Shiou-Hwei Yeh
- Department of Microbiology, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan.,NTU Center for Genomic Medicine, National Taiwan University Hospital and National Taiwan University, College of Medicine, Taipei, Taiwan
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35
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Li P, Gao Y, Li F, Pan Q, Liu Z, Lu X, Song C, Diao X. MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1α. Exp Ther Med 2015; 10:1165-1170. [PMID: 26622458 DOI: 10.3892/etm.2015.2630] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2015] [Accepted: 06/24/2015] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effects of microRNA-18a (miR-18a) on the invasiveness and metastasis of invasive meningiomas and the underlying mechanism. A total of 69 patients with meningiomas (30 patients in the invasive meningioma group and 39 patients in the non-invasive meningioma group) and 48 cases in the control group were enrolled. Samples of meningioma tissues, serum and cerebrospinal fluid were collected. Reverse transcription-quantitative polymerase chain reaction was performed to quantify the expression levels of hypoxia-inducible factor-1α (HIF-1α) mRNA and miR-18a. Western blot analysis was used to determine protein expression levels of HIF-1α. The expression levels of HIF-1α mRNA and protein in all three types of sample from the invasive meningioma group were significantly higher compared with those in the control and non-invasive meningioma groups (P<0.05), and the expression levels of HIF-1α mRNA in the serum and cerebrospinal fluid of the non-invasive meningioma group were significantly higher compared with those in the control group (P<0.05). The expression levels of miR-18a in the invasive meningioma group were significantly reduced compared with those in the control and non-invasive meningioma groups (P<0.05), whereas the levels of miR-18a in the non-invasive meningioma group were significantly lower compared with those in the control group (P<0.05). The expression of HIF-1α is significantly upregulated in patients with invasive meningiomas, possibly due to the downregulation of miR-18a expression. Therefore, miR-18a may regulate invasive meningiomas via HIF-1α.
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Affiliation(s)
- Puxian Li
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Yong Gao
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Fengjia Li
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Qiang Pan
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Zhenrui Liu
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Xiangdong Lu
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Chunyu Song
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
| | - Xingtao Diao
- Department of Neurosurgery, Laiwu City People's Hospital, Laiwu, Shandong 271100, P.R. China
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36
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Abstract
There are numerous physiologic and biochemical changes in menopause that can affect the function of the liver and mediate the development of liver disease. Menopause represents a state of growing estrogen deficiency, and this loss of estrogen in the setting of physiologic aging increases the likelihood of mitochondrial dysfunction, cellular senescence, declining immune responses to injury, and disarray in the balance between antioxidant formation and oxidative stress. The sum effect of these changes can contribute to increased susceptibility to development of significant liver pathology, particularly nonalcoholic fatty liver disease and hepatocellular carcinoma, as well as accelerated progression of fibrosis in liver diseases, as has been particularly demonstrated in hepatitis C virus liver disease. Recognition of the unique nature of these mediating factors should raise suspicion for liver disease in perimenopausal and menopausal women and offer an opportunity for implementation of aggressive treatment measures so as to avoid progression of liver disease to cirrhosis, liver cancer and liver failure.
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37
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Yuan B, Liang Y, Wang D, Luo F. MiR-940 inhibits hepatocellular carcinoma growth and correlates with prognosis of hepatocellular carcinoma patients. Cancer Sci 2015; 106:819-24. [PMID: 25940592 PMCID: PMC4520632 DOI: 10.1111/cas.12688] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 04/01/2015] [Accepted: 04/27/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related death in China. Deregulation of microRNA (miRNA) contributes to HCC development by influencing cell growth, apoptosis, migration or invasion. It has been proved that miR-940 plays important roles in various cancers. Here we investigated the role of miR-940 in HCC. We found that miR-940 was remarkably decreased in HCC tissues and cell lines. Importantly, lower miR-940 expression in HCC tissues significantly correlated with the reduced patient's survival rate. Overexpression of miR-940 inhibited HCC cell line growth and induced cell apoptosis, and vice versa. Estrogen-related receptor gamma (ESRRG) was targeted by miR-940, and suppression of ESRRG inhibited HCC cell lines growth and induced cell apoptosis. In conclusion, we found that a lower level of miR-940 in HCC promoted cellular proliferation via ESRRG, which may lead to the short survival period of HCC patients.
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Affiliation(s)
- Bo Yuan
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Yasha Liang
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Duoning Wang
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
| | - Fengming Luo
- Department of General Practice, West China Hospital, Sichuan University, Chengdu, China
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38
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Montella M, D'Arena G, Crispo A, Capunzo M, Nocerino F, Grimaldi M, Barbieri A, D'Ursi AM, Tecce MF, Amore A, Galdiero M, Ciliberto G, Giudice A. Role of Sex Hormones in the Development and Progression of Hepatitis B Virus-Associated Hepatocellular Carcinoma. Int J Endocrinol 2015; 2015:854530. [PMID: 26491442 PMCID: PMC4600563 DOI: 10.1155/2015/854530] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 06/29/2015] [Accepted: 07/01/2015] [Indexed: 12/25/2022] Open
Abstract
Infection with hepatitis B virus (HBV) is a major risk factor for hepatocellular carcinoma (HCC) in developed countries. Epidemiological reports indicate that the incidence of HBV-related HCC is higher in males and postmenopausal females than other females. Increasing evidence suggests that sex hormones such as androgens and estrogens play an important role in the progression of an HBV infection and in the development of HBV-related HCC. While androgen is supposed to stimulate the androgen signaling pathway and cooperate to the increased transcription and replication of HBV genes, estrogen may play a protecting role against the progression of HBV infections and in the development of HBV-related HCC through decreasing HBV RNA transcription and inflammatory cytokines levels. Additionally, sex hormones can also affect HBV-related hepatocarcinogenesis by inducing epigenetic changes such as the regulation of mRNA levels by microRNAs (miRNAs), DNA methylation, and histone modification in liver tissue. This review describes the molecular mechanisms underlying the gender disparity in HBV-related HCC with the aim of improving the understanding of key factors underneath the sex disparity often observed in HBV infections. Furthermore, the review will propose more effective prevention strategies and treatments of HBV-derived diseases.
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Affiliation(s)
- Maurizio Montella
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
- *Maurizio Montella:
| | - Giovanni D'Arena
- Department of Onco-Hematology, IRCCS, Cancer Referral Center of Basilicata, 85028 Rionero in Vulture, Italy
| | - Anna Crispo
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Mario Capunzo
- Department of Medicine and Surgery, University of Salerno, 84081 Fisciano, Italy
| | - Flavia Nocerino
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Maria Grimaldi
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Antonio Barbieri
- Animal Facility, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Anna Maria D'Ursi
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Mario Felice Tecce
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Salerno, Italy
| | - Alfonso Amore
- Department of Surgery, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | | | - Gennaro Ciliberto
- National Cancer Institute “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
| | - Aldo Giudice
- Epidemiology Unit, National Cancer Institute of Naples “G. Pascale Foundation”, IRCCS, 80131 Naples, Italy
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Zhao Q, Li T, Qi J, Liu J, Qin C. The miR-545/374a cluster encoded in the Ftx lncRNA is overexpressed in HBV-related hepatocellular carcinoma and promotes tumorigenesis and tumor progression. PLoS One 2014; 9:e109782. [PMID: 25299640 PMCID: PMC4192320 DOI: 10.1371/journal.pone.0109782] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 09/02/2014] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Previous studies have shown several long noncoding RNAs (lncRNAs) play various roles in HCC progression, but no research has focused on the expression pattern of microRNA clusters encoded in lncRNAs. The Ftx gene encodes a lncRNA which harbors 2 clusters of microRNAs in its introns, the miR-374b/421 cluster and the miR-545/374a cluster. To date, no research has focused on the role of the miR-545/374a and miR-374b/421 clusters in HBV-related HCC. In this study, 66 pairs of HBV-related HCC tissue and matched non-cancerous liver tissue specimens were analyzed for the expression of the Ftx microRNA clusters. Our results showed that the miR-545/374a cluster was upregulated in HBV-HCC tissue and significantly correlated with prognosis-related clinical features, including histological grade, metastasis and tumor capsule. Transfection studies with microRNA mimics and inhibitors revealed that miR-545/374a expression promoted in vitro cell proliferation, cell migration and invasion. The wild-type HBV-genome-containing plasmid or full-length HBx protein encoding plasmid was transfected into the Bel-7402 cell line and observed for their influence on miR-545/374a expression. We found that transfection of the HBV genome or HBx alone resulted in an increase in miR-545/374a expression. Next, by monitoring the expression of sera miR-545/374a before and after surgical tumor excision, we found serum miR-545/374a was tumor-derived and exhibited a sharp decrease 25 days after tumor excision. We also examined the gender-based difference in miR-545/374a expression among HCC patients and utilized microRNA target prediction software to find the targets of miR-545/374a. One of these targets, namely estrogen-related receptor gamma (ESRRG) was inversely correlated with miR-545 expression. In conclusion, the overexpression of miR-545/374a cluster located in the Ftx lncRNA is partially responsible for a poor prognosis, and monitoring sera levels of miR-545/374a may be a useful diagnostic marker for HCC.
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MESH Headings
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/surgery
- Carcinoma, Hepatocellular/virology
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Disease Progression
- Female
- Gene Expression Regulation, Neoplastic
- Hepatitis B/complications
- Hepatitis B/genetics
- Hepatitis B/surgery
- Hepatitis B/virology
- Hepatitis B virus/genetics
- Hepatitis B virus/pathogenicity
- Humans
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/surgery
- Liver Neoplasms/virology
- Male
- MicroRNAs/blood
- MicroRNAs/genetics
- Middle Aged
- Prognosis
- RNA, Long Noncoding/blood
- RNA, Long Noncoding/genetics
- Receptors, Estrogen/genetics
- Receptors, Estrogen/metabolism
- Signal Transduction
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Transfection
- Viral Regulatory and Accessory Proteins
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Affiliation(s)
- Qi Zhao
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Tao Li
- Department of Infectious Diseases, Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Jianni Qi
- Central Laboratory, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
| | - Juan Liu
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Chengyong Qin
- Department of Gastroenterology, Provincial Hospital Affiliated to Shandong University, Jinan, China
- * E-mail:
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40
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Li B, Huang P, Qiu J, Liao Y, Hong J, Yuan Y. MicroRNA-130a is down-regulated in hepatocellular carcinoma and associates with poor prognosis. Med Oncol 2014; 31:230. [PMID: 25218269 DOI: 10.1007/s12032-014-0230-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Accepted: 09/03/2014] [Indexed: 12/16/2022]
Abstract
MicroRNA-130a (miR-130a) has recently been found to be implicated in many critical processes in various types of human cancer. However, the prognostic value of miR-130a in hepatocellular carcinoma (HCC) remains unclear. In the present study, we investigated the expression of miR-130a in HCC and analyzed its association with clinical features and prognosis of HCC patients. We determined the expression level of miR-130a in 102 cases of paired HCC and adjacent non-tumor tissues by quantitative real-time PCR (qRT-PCR). The qRT-PCR results showed that the miR-130a expression was significantly down-regulated in tumor tissues compared with the adjacent non-tumor tissues (P<0.001). Correlation analysis showed that miR-130a expression was significantly correlated with gender (P=0.008), HBsAg status (P=0.038), tumor size (P=0.003), and tumor-node-metastasis stage (P=0.029). Kaplan-Meier analysis showed that patients with low miR-130a expression had a poorer overall survival than patients with high miR-130a expression (log-rank P=0.007). The multivariate Cox regression analysis indicated that miR-130a expression was an independent prognostic factor for overall survival (hazard ratio 2.217; 95% CI 1.103-4.458; P=0.025). The present study showed for the first time that miR-130a expression was significantly down-regulated in HCC and associated with overall survival of patients with HCC. The present study also provided evidence that miR-130a was an independent prognostic factor and could serve as a potential prognostic biomarker for patients with HCC.
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Affiliation(s)
- Binkui Li
- State Key Laboratory of Oncology in South China, Guangzhou, China
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