|
1
|
Sivasudhan E, Zhou J, Ma J, Wang Y, Liu S, Khan FI, Lu Z, Meng J, Blake N, Rong R. Hepatitis B Virus X Protein Contributes to Hepatocellular Carcinoma via Upregulation of KIAA1429 Methyltransferase and mRNA m6A Hypermethylation of HSPG2/Perlecan. Mol Carcinog 2025; 64:108-125. [PMID: 39412412 DOI: 10.1002/mc.23830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 09/12/2024] [Accepted: 09/27/2024] [Indexed: 12/13/2024]
Abstract
Chronic hepatitis B virus (HBV) remains to be the most common risk factor of hepatocellular carcinoma (HCC). While previous work has primarily focussed on understanding the direct and indirect mechanisms of Hepatitis B virus X protein (HBx)-mediated hepatocarcinogenesis, from genetic and epigenetic perspectives, its influence on RNA modification mediated onset of liver malignancies is less well understood. This study explored the role of HBV-encoded HBx in altering the m6A methylome profile and its implications on the pathogenesis of HCC. We established HBx-expressing stable HCC cell lines, Huh7-HBx and HepG2-HBx, and explored the transcriptomic and epitranscriptomic profiles by RNA-seq and MeRIP-seq, respectively. Preliminary results suggest that HBx promotes liver cell proliferation, migration, survival and overall m6A methylation in HCC cells and is involved in modulating the extracellular matrix. We show that HBx mediates liver cell transformation by upregulating KIAA1429 methyltransferase. HBx also drives the expression and hypermethylation of the extracellular matrix protein HSPG2/Perlecan and promotes tumourigenesis. Furthermore, we observed a potential interaction between KIAA1429 and HSPG2 in HCC liver cancer cells and demands further investigation.
Collapse
MESH Headings
- Humans
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/virology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Viral Regulatory and Accessory Proteins
- Liver Neoplasms/genetics
- Liver Neoplasms/virology
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Gene Expression Regulation, Neoplastic
- Heparan Sulfate Proteoglycans/metabolism
- Heparan Sulfate Proteoglycans/genetics
- Hepatitis B virus/genetics
- Cell Proliferation
- Up-Regulation
- DNA Methylation
- RNA, Messenger/genetics
- Animals
- Cell Line, Tumor
- Mice
- Methyltransferases/metabolism
- Methyltransferases/genetics
- Hep G2 Cells
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/metabolism
- Hepatitis B, Chronic/virology
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/complications
- Cell Movement/genetics
- RNA-Binding Proteins
Collapse
Affiliation(s)
- Enakshi Sivasudhan
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Jingxian Zhou
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- School of AI and Advanced Computing, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Computer Science, University of Liverpool, Liverpool, UK
| | - Jiongming Ma
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Yuanyuan Wang
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Siying Liu
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, China
| | - Faez Iqbal Khan
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Zhiliang Lu
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Jia Meng
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK
| | - Neil Blake
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| | - Rong Rong
- Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Suzhou Municipal Key Lab of Cancer Biology and Chronic Disease, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
- Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, UK
| |
Collapse
|
|
2
|
Hu J, Xu H, Ma X, Bai M, Zhou Y, Miao R, Wang F, Li X, Cheng B. Modulating PCGF4/BMI1 Stability Is an Efficient Metastasis-Regulatory Strategy Used by Distinct Subtypes of Cancer-Associated Fibroblasts in Intrahepatic Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:1388-1404. [PMID: 38670529 DOI: 10.1016/j.ajpath.2024.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 02/17/2024] [Accepted: 03/21/2024] [Indexed: 04/28/2024]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is a highly malignant neoplasm prone to metastasis. Whether cancer-associated fibroblasts (CAFs) affect the metastasis of ICC is unclear. Herein, ICC patient-derived CAF lines and related cancerous cell lines were established and the effects of CAFs on the tumor progressive properties of the ICC cancerous cells were analyzed. CAFs could be classified into cancer-restraining or cancer-promoting categories based on distinct tumorigenic effects. The RNA-sequencing analyses of ICC cancerous cell lines identified polycomb group ring finger 4 (PCGF4; alias BMI1) as a potential metastasis regulator. The changes of PCGF4 levels in ICC cells mirrored the restraining or promoting effects of CAFs on ICC migration. Immunohistochemical analyses on the ICC tissue microarrays indicated that PCGF4 was negatively correlated with overall survival of ICC. The promoting effects of PCGF4 on cell migration, drug resistance activity, and stemness properties were confirmed. Mechanistically, cancer-restraining CAFs triggered the proteasome-dependent degradation of PCGF4, whereas cancer-promoting CAFs enhanced the stability of PCGF4 via activating the IL-6/phosphorylated STAT3 pathway. In summary, the current data identified the role of CAFs in ICC metastasis and revealed a new mechanism of the CAFs on ICC progression in which PCGF4 acted as the key effector by both categories of CAFs. These findings shed light on developing comprehensive therapeutic strategies for ICC.
Collapse
Affiliation(s)
- Jinjing Hu
- School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Hao Xu
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xiaojun Ma
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Mingzhen Bai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Yongqiang Zhou
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Ruidong Miao
- School of Life Sciences, Lanzhou University, Lanzhou, China
| | - Fanghong Wang
- The Fourth Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China; The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China; Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China.
| | - Bo Cheng
- School of Life Sciences, Lanzhou University, Lanzhou, China; Key Laboratory of Cell Activities and Stress Adaptations, Ministry of Education, Lanzhou University, Lanzhou, China.
| |
Collapse
|
|
3
|
Xue X, Li Y, Yao Y, Zhang S, Peng C, Li Y. A comprehensive review of miR-21 in liver disease: Big impact of little things. Int Immunopharmacol 2024; 134:112116. [PMID: 38696909 DOI: 10.1016/j.intimp.2024.112116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 04/10/2024] [Accepted: 04/17/2024] [Indexed: 05/04/2024]
Abstract
microRNAs (miRNAs), a class of non-coding RNA with 20-24 nucleotides, are defined as the powerful regulators for gene expression. miR-21 is a multifunctional miRNA enriched in the circulatory system and multiple organs, which not only serves as a non-invasive biomarker in disease diagnosis, but also participates in many cellular activities. In various chronic liver diseases, the increase of miR-21 affects glycolipid metabolism, viral infection, inflammatory and immune cell activation, hepatic stellate cells activation and tissue fibrosis, and autophagy. Moreover, miR-21 is also a liaison in the deterioration of chronic liver disease to hepatocellular carcinoma (HCC), and it impacts on cell proliferation, apoptosis, migration, invasion, angiogenesis, immune escape, and epithelial-mesenchymal transformation by regulating target genes expression in different signaling pathways. In current research on miRNA therapy, some natural products can exert the hepatoprotective effects depending on the inhibition of miR-21 expression. In addition, miR-21-based therapeutic also play a role in regulating intracellular miR-21 levels and enhancing the efficacy of chemotherapy drugs. Herein, we systemically summarized the recent progress of miR-21 on biosynthesis, biomarker function, molecular mechanism and miRNA therapy in chronic liver disease and HCC, and looked forward to outputting some information to enable it from bench to bedside.
Collapse
Affiliation(s)
- Xinyan Xue
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yanzhi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yuxin Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Shenglin Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yunxia Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Key Laboratory of Standardization for Chinese Herbal Medicine, Ministry of Education, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| |
Collapse
|
|
4
|
Younis MA, Harashima H. Understanding Gene Involvement in Hepatocellular Carcinoma: Implications for Gene Therapy and Personalized Medicine. Pharmgenomics Pers Med 2024; 17:193-213. [PMID: 38737776 PMCID: PMC11088404 DOI: 10.2147/pgpm.s431346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 04/09/2024] [Indexed: 05/14/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the dominant type of liver cancers and is one of the deadliest health threats globally. The conventional therapeutic options for HCC are hampered by low efficiency and intolerable side effects. Gene therapy, however, now offers hope for the treatment of many disorders previously considered incurable, and gene therapy is beginning to address many of the shortcomings of conventional therapies. Herein, we summarize the involvement of genes in the pathogenesis and prognosis of HCC, with a special focus on dysregulated signaling pathways, genes involved in immune evasion, and non-coding RNAs as novel two-edged players, which collectively offer potential targets for the gene therapy of HCC. Herein, the opportunities and challenges of HCC gene therapy are discussed. These include innovative therapies such as genome editing and cell therapies. Moreover, advanced gene delivery technologies that recruit nanomedicines for use in gene therapy for HCC are highlighted. Finally, suggestions are offered for improved clinical translation and future directions in this area of endeavor.
Collapse
Affiliation(s)
- Mahmoud A Younis
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hideyoshi Harashima
- Laboratory of Innovative Nanomedicine, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Toll- like receptor 2 polymorphism and IL-6 profile in relation to disease progression in chronic HBV infection: a case control study in Egyptian patients. Clin Exp Med 2023; 23:117-129. [PMID: 35119591 PMCID: PMC9939497 DOI: 10.1007/s10238-022-00792-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/04/2022] [Indexed: 11/03/2022]
Abstract
Chronic hepatitis B (CHB) has a wide range of outcomes depending on host immune responses mainly Toll-like receptors (TLRs) signaling and released cytokines. Toll-like receptor 2 (TLR2) single nucleotide polymorphisms (SNPs) and interleukin 6 (IL-6) may influence the course of CHB. We aimed to elucidate the relation between TLR-2 polymorphism, IL-6 profile, and CHB progression. We analyzed TLR-2 polymorphism (SNP; rs3804099) in 185 CHB patients and 60 controls using TaqMan allelic discrimination assay. Serum IL-6 levels were assessed by ELISA. IL-6 levels were considerably higher in active CHB and cirrhotic patients compared with inactive carriers and controls (P < 0.001). IL-6 showed positive correlation with ALT and advanced fibrosis in active CHB patients (r = 0.31, P = 0.02). A significant positive correlation was noticed between IL-6 and HBV DNA PCR in all CHB groups. TT genotype of rs3804099/TLR-2 was significantly more prevalent in inactive carriers compared to active hepatitis patients (P = 0.04, OR = 0.39 and 95% CI: 0.16-0.95). Both heterozygous CT and mutant TT genotypes were significantly more frequent among inactive carriers compared to cirrhotic patients (P = 0.01, OR = 0.33, 95% CI: 0.13-0.81 and P = 0.009, OR = 0.32, 95% CI: 0.13-0.77). TT genotype was significantly related to lower IL-6 levels in active hepatitis and cirrhotic groups (P = 0.005 and P = 0.001, respectively) showing that TLR mutations would be associated with milder hepatitis activity and lower possibility for disease progression. There may be a positive association between TLR2 rs3804099 polymorphism and hepatitis B activity. IL-6 is a good indicator of CHB disease progression.
Collapse
|
|
7
|
Micro-Players of Great Significance-Host microRNA Signature in Viral Infections in Humans and Animals. Int J Mol Sci 2022; 23:ijms231810536. [PMID: 36142450 PMCID: PMC9504570 DOI: 10.3390/ijms231810536] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/04/2022] [Accepted: 09/08/2022] [Indexed: 11/22/2022] Open
Abstract
Over time, more and more is becoming known about micro-players of great significance. This is particularly the case for microRNAs (miRNAs; miR), which have been found to participate in the regulation of many physiological and pathological processes in both humans and animals. One such process is viral infection in humans and animals, in which the host miRNAs—alone or in conjunction with the virus—interact on two levels: viruses may regulate the host’s miRNAs to evade its immune system, while the host miRNAs can play anti- or pro-viral roles. The purpose of this comprehensive review is to present the key miRNAs involved in viral infections in humans and animals. We summarize the data in the available literature, indicating that the signature miRNAs in human viral infections mainly include 12 miRNAs (i.e., miR-155, miR-223, miR-146a, miR-122, miR-125b, miR-132, miR-34a, miR -21, miR-16, miR-181 family, let-7 family, and miR-10a), while 10 miRNAs are commonly found in animals (i.e., miR-155, miR-223, miR-146a, miR-145, miR-21, miR-15a/miR-16 cluster, miR-181 family, let-7 family, and miR-122) in this context. Knowledge of which miRNAs are involved in different viral infections and the biological functions that they play can help in understanding the pathogenesis of viral diseases, facilitating the future development of therapeutic agents for both humans and animals.
Collapse
|
|
8
|
Zhao F, Xie X, Tan X, Yu H, Tian M, Lv H, Qin C, Qi J, Zhu Q. The Functions of Hepatitis B Virus Encoding Proteins: Viral Persistence and Liver Pathogenesis. Front Immunol 2021; 12:691766. [PMID: 34456908 PMCID: PMC8387624 DOI: 10.3389/fimmu.2021.691766] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
About 250 million people worldwide are chronically infected with Hepatitis B virus (HBV), contributing to a large burden on public health. Despite the existence of vaccines and antiviral drugs to prevent infection and suppress viral replication respectively, chronic hepatitis B (CHB) cure remains a remote treatment goal. The viral persistence caused by HBV is account for the chronic infection which increases the risk for developing liver cirrhosis and hepatocellular carcinoma (HCC). HBV virion utilizes various strategies to escape surveillance of host immune system therefore enhancing its replication, while the precise mechanisms involved remain elusive. Accumulating evidence suggests that the proteins encoded by HBV (hepatitis B surface antigen, hepatitis B core antigen, hepatitis B envelope antigen, HBx and polymerase) play an important role in viral persistence and liver pathogenesis. This review summarizes the major findings in functions of HBV encoding proteins, illustrating how these proteins affect hepatocytes and the immune system, which may open new venues for CHB therapies.
Collapse
Affiliation(s)
- Fenglin Zhao
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Xiaoyu Xie
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xu Tan
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hongli Yu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China
| | - Miaomiao Tian
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Huanran Lv
- Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengyong Qin
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jianni Qi
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Zhu
- Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.,Shandong Provincial Engineering and Technological Research Center for Liver Diseases Prevention and Control, Jinan, China.,Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.,The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| |
Collapse
|
|
9
|
Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
Collapse
Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
| |
Collapse
|
|
10
|
He G, Ding J, Zhang Y, Cai M, Yang J, Cho WC, Zheng Y. microRNA-21: a key modulator in oncogenic viral infections. RNA Biol 2021; 18:809-817. [PMID: 33499700 PMCID: PMC8078529 DOI: 10.1080/15476286.2021.1880756] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 12/12/2020] [Accepted: 01/20/2021] [Indexed: 10/22/2022] Open
Abstract
Oncogenic viruses are associated with approximately 15% of human cancers. In viral infections, microRNAs play an important role in host-pathogen interactions. miR-21 is a highly conserved non-coding RNA that not only regulates the development of oncogenic viral diseases, but also responds to the regulation of intracellular signal pathways. Oncogenic viruses, including HBV, HCV, HPV, and EBV, co-evolve with their hosts and cause persistent infections. The upregulation of host miR-21 manipulates key cellular pathways to evade host immune responses and then promote viral replication. Thus, a better understanding of the role of miR-21 in viral infections may help us to develop effective genetically-engineered oncolytic virus-based therapies against cancer.
Collapse
Affiliation(s)
- Guitian He
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Juntao Ding
- College of Life Science and Technology, College of Life Science and Technology, Xinjiang University, Urumqi, China
| | - Yong’e Zhang
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Mengting Cai
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - Jing Yang
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
| | - William C. Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
| | - Yadong Zheng
- State Key Laboratory of Veterinary Etiological Biology' and 'Key Laboratory of Veterinary Parasitology of Gansu Province, CAAS, Lanzhou, China
- Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, YangzhouChina
| |
Collapse
|
|
11
|
Sekiba K, Otsuka M, Koike K. Potential of HBx Gene for Hepatocarcinogenesis in Noncirrhotic Liver. Semin Liver Dis 2021; 41:142-149. [PMID: 33984871 DOI: 10.1055/s-0041-1723033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Current treatments for hepatitis B virus (HBV) using nucleos(t)ide analogs cannot eliminate the risk of hepatocellular carcinoma (HCC) development. As HBV-associated HCC can develop even in the absence of liver cirrhosis, HBV is regarded to possess direct oncogenic potential. HBV regulatory protein X (HBx) has been identified as a primary mediator of HBV-mediated hepatocarcinogenesis. A fragment of the HBV genome that contains the coding region of HBx is commonly integrated into the host genome, resulting in the production of aberrant proteins and subsequent hepatocarcinogenesis. Besides, HBx interferes with the host DNA or deoxyribonucleic acid damage repair pathways, signal transduction, epigenetic regulation of gene expression, and cancer immunity, thereby promoting carcinogenesis in the noncirrhotic liver. However, numerous molecules and pathways have been implicated in the development of HBx-associated HCC, suggesting that the mechanisms underlying HBx-mediated hepatocarcinogenesis remain to be elucidated.
Collapse
Grants
- Japan Agency for Medical Research and Development, AMED JP20fk0210054
- Japan Agency for Medical Research and Development, AMED JP20fk0210080h0001
- Japan Agency for Medical Research and Development, AMED JP20fk0310102
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19H03430
- The Ministry of Education, Culture, Sports, Science, and Technology, Japan 19J11829
Collapse
Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
12
|
Zeisel MB, Guerrieri F, Levrero M. Host Epigenetic Alterations and Hepatitis B Virus-Associated Hepatocellular Carcinoma. J Clin Med 2021; 10:jcm10081715. [PMID: 33923385 PMCID: PMC8071488 DOI: 10.3390/jcm10081715] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/06/2021] [Accepted: 04/12/2021] [Indexed: 12/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent primary malignancy of the liver and a leading cause of cancer-related deaths worldwide. Although much progress has been made in HCC drug development in recent years, treatment options remain limited. The major cause of HCC is chronic hepatitis B virus (HBV) infection. Despite the existence of a vaccine, more than 250 million individuals are chronically infected by HBV. Current antiviral therapies can repress viral replication but to date there is no cure for chronic hepatitis B. Of note, inhibition of viral replication reduces but does not eliminate the risk of HCC development. HBV contributes to liver carcinogenesis by direct and indirect effects. This review summarizes the current knowledge of HBV-induced host epigenetic alterations and their association with HCC, with an emphasis on the interactions between HBV proteins and the host cell epigenetic machinery leading to modulation of gene expression.
Collapse
Affiliation(s)
- Mirjam B. Zeisel
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
- Correspondence: (M.B.Z.); (M.L.)
| | - Francesca Guerrieri
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France;
- Hospices Civils de Lyon, Hôpital Croix Rousse, Service d’Hépato-Gastroentérologie, 69004 Lyon, France
- Correspondence: (M.B.Z.); (M.L.)
| |
Collapse
|
|
13
|
MicroRNA Interference in Hepatic Host-Pathogen Interactions. Int J Mol Sci 2021; 22:ijms22073554. [PMID: 33808062 PMCID: PMC8036276 DOI: 10.3390/ijms22073554] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 03/24/2021] [Accepted: 03/27/2021] [Indexed: 12/14/2022] Open
Abstract
The liver is well recognized as a non-immunological visceral organ that is involved in various metabolic activities, nutrient storage, and detoxification. Recently, many studies have demonstrated that resident immune cells in the liver drive various immunological reactions by means of several molecular modulators. Understanding the mechanistic details of interactions between hepatic host immune cells, including Kupffer cells and lymphocytes, and various hepatic pathogens, especially viruses, bacteria, and parasites, is necessary. MicroRNAs (miRNAs), over 2600 of which have been discovered, are small, endogenous, interfering, noncoding RNAs that are predicted to regulate more than 15,000 genes by degrading specific messenger RNAs. Several recent studies have demonstrated that some miRNAs are associated with the immune response to pathogens in the liver. However, the details of the underlying mechanisms of miRNA interference in hepatic host-pathogen interactions still remain elusive. In this review, we summarize the relationship between the immunological interactions of various pathogens and hepatic resident immune cells, as well as the role of miRNAs in the maintenance of liver immunity against pathogens.
Collapse
|
|
14
|
Abstract
Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). There are approximately 250 million people in the world that are chronically infected by this virus, resulting in nearly 1 million deaths every year. Many of these patients die from severe liver diseases, including HCC. HBV may induce HCC through the induction of chronic liver inflammation, which can cause oxidative stress and DNA damage. However, many studies also indicated that HBV could induce HCC via the alteration of hepatocellular physiology that may involve genetic and epigenetic changes of the host DNA, the alteration of cellular signaling pathways, and the inhibition of DNA repair mechanisms. This alteration of cellular physiology can lead to the accumulation of DNA damages and the promotion of cell cycles and predispose hepatocytes to oncogenic transformation.
Collapse
Affiliation(s)
- Jiyoung Lee
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Kuen-Nan Tsai
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA
| | - Jing-Hsiung James Ou
- Department of Molecular Microbiology and Immunology, University of Southern California Keck School of Medicine, 2011 Zonal Avenue, HMR-401, Los Angeles, CA, 90033, USA.
| |
Collapse
|
|
15
|
Loureiro D, Tout I, Narguet S, Benazzouz SM, Mansouri A, Asselah T. miRNAs as Potential Biomarkers for Viral Hepatitis B and C. Viruses 2020; 12:E1440. [PMID: 33327640 PMCID: PMC7765125 DOI: 10.3390/v12121440] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.
Collapse
Affiliation(s)
| | | | | | | | | | - Tarik Asselah
- Department of Hepatology, Université de Paris, CRI, INSERM UMR 1149, AP-HP Hôpital Beaujon, 92110 Clichy, France; (D.L.); (I.T.); (S.N.); (S.M.B.); (A.M.)
| |
Collapse
|
|
16
|
The miR-21 potential of serving as a biomarker for liver diseases in clinical practice. Biochem Soc Trans 2020; 48:2295-2305. [PMID: 33119045 DOI: 10.1042/bst20200653] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 09/18/2020] [Accepted: 10/05/2020] [Indexed: 12/11/2022]
Abstract
The role of miR-21 in the pathogenesis of various liver diseases, together with the possibility of detecting microRNA in the circulation, makes miR-21 a potential biomarker for noninvasive detection. In this review, we summarize the potential utility of extracellular miR-21 in the clinical management of hepatic disease patients and compared it with the current clinical practice. MiR-21 shows screening and prognostic value for liver cancer. In liver cirrhosis, miR-21 may serve as a biomarker for the differentiating diagnosis and prognosis. MiR-21 is also a potential biomarker for the severity of hepatitis. We elucidate the disease condition under which miR-21 testing can reach the expected performance. Though miR-21 is a key regulator of liver diseases, microRNAs coordinate with each other in the complex regulatory network. As a result, the performance of miR-21 is better when combined with other microRNAs or classical biomarkers under certain clinical circumstances.
Collapse
|
|
17
|
Wang Y, Zhang P, Yuan M, Li X. Overexpression of miRNA-21 Promotes the Proliferation and Invasion in Hepatocellular Carcinoma Cells via Suppressing SMAD7. Technol Cancer Res Treat 2020; 18:1533033819878686. [PMID: 31554487 PMCID: PMC6763940 DOI: 10.1177/1533033819878686] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Purpose: This study aimed to explore the molecular mechanism of microRNA-21 and smad family member 7 in hepatocellular carcinoma. Method: A total of 57 participants were divided into control group (healthy participants, n = 10) and hepatocellular carcinoma group (hepatocellular carcinoma patients, n = 37). The expression of microRNA-21 levels were first detected in these two groups. Cell transfection was performed on hepatoma cell lines, followed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assay to reveal proliferation and invasion ability. Furthermore, the relation between microRNA-21 and smad family member 7 was revealed by luciferase reporter gene and RNA immunoprecipitation assay. Finally, a transplantation tumor model of breast cancer in mice was constructed. Results: The serum indicators including α-alanine aminotransferase, aspartate aminotransferase, and albumin were differentially expressed between hepatocellular carcinoma group and control group. Compared to the control group, there was a high expression of microRNA-21 in hepatocellular carcinoma group. Low expression of microRNA-21 inhibited the proliferation and invasion of HepG2.2.15 and Huh7-1.3 cells. Luciferase reporter gene and RNA innumoprecipitation assay showed that smad family member 7 was the target gene of microRNA-21. Moreover, mice model analysis showed that microRNA-21 might regulate the growth of the transplanted tumors in mice by targeting smad family member 7. Conclusion: The upregulated microRNA-21 might participate in the proliferation and migration in cells of hepatocellular carcinoma via suppression of smad family member 7. Furthermore, serum indicators such as alanine aminotransferase, aspartate aminotransferase, and albumin might be used as serum diagnostic markers for hepatocellular carcinoma.
Collapse
Affiliation(s)
- Yan Wang
- Chronic Disease Management Center, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Ping Zhang
- Department of Clinical Lab, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Mei Yuan
- Department of Clinical Lab, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| | - Xiaojie Li
- Department of The 7th Inpatient Ward, Qingdao Sixth People's Hospital, Qingdao City, Shandong Province, China
| |
Collapse
|
|
18
|
Zhang T, Yang Z, Kusumanchi P, Han S, Liangpunsakul S. Critical Role of microRNA-21 in the Pathogenesis of Liver Diseases. Front Med (Lausanne) 2020; 7:7. [PMID: 32083086 PMCID: PMC7005070 DOI: 10.3389/fmed.2020.00007] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 01/10/2020] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs are small non-coding RNAs that range in length from 18 to 24 nucleotides. As one of the most extensively studied microRNAs, microRNA-21 (miR-21) is highly expressed in many mammalian cell types. It regulates multiple biological functions such as proliferation, differentiation, migration, and apoptosis. In this review, we summarized the mechanism of miR-21 in the pathogenesis of various liver diseases. While it is clear that miR-21 plays an important role in different types of liver diseases, its use as a diagnostic marker for specific liver disease or its therapeutic implication are not ready for prime time due to significant variability and heterogeneity in the expression of miR-21 in different types of liver diseases depending on the studies. Additional studies to further define miR-21 functions and its mechanism in association with each type of chronic liver diseases are needed before we can translate the bedside observations into clinical settings.
Collapse
Affiliation(s)
- Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Center for Liver Research, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Center for Liver Research, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Center for Liver Research, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Center for Liver Research, Department of Medicine, Indiana University, Indianapolis, IN, United States
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States.,Indiana Center for Liver Research, Department of Medicine, Indiana University, Indianapolis, IN, United States.,Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
| |
Collapse
|
|
19
|
Deng Y, Wei Z, Huang M, Xu G, Wei W, Peng B, Nong S, Qin H. Long non-coding RNA F11-AS1 inhibits HBV-related hepatocellular carcinoma progression by regulating NR1I3 via binding to microRNA-211-5p. J Cell Mol Med 2019; 24:1848-1865. [PMID: 31880390 PMCID: PMC6991646 DOI: 10.1111/jcmm.14881] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2019] [Revised: 09/17/2019] [Accepted: 10/28/2019] [Indexed: 12/25/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) could regulate growth and metastasis of hepatocellular carcinoma (HCC). In this study, we aimed to investigate the mechanism of lncRNA F11-AS1 in hepatitis B virus (HBV)-related HCC. The relation of lncRNA F11-AS1 expression in HBV-related HCC tissues to prognosis was analysed in silico. Stably HBV-expressing HepG2.2.15 cells were established to explore the regulation of lncRNA F11-AS1 by HBx protein, as well as to study the effects of overexpressed lncRNA F11-AS1 on proliferation, migration, invasion and apoptosis in vitro. Subsequently, the underlying interactions and roles of lncRNA F11-AS1/miR-211-5p/NR1I3 axis in HBV-related HCC were investigated. Additionally, the influence of lncRNA F11-AS1 and miR-211-5p on tumour growth and metastasis capacity of HepG2.2.15 cells were studied on tumour-bearing nude mice. Poor expression of lncRNA F11-AS1 was correlated with poor prognosis in patients with HBV-related HCC, and its down-regulation was caused by the HBx protein. lncRNA F11-AS1 was proved to up-regulate the NR1I3 expression by binding to miR-211-5p. Overexpression of lncRNA F11-AS1 reduced the proliferation, migration and invasion, yet induced apoptosis of HepG2.2.15 cells in vitro, which could be abolished by overexpression of miR-211-5p. Additionally, either lncRNA F11-AS1 overexpression or miR-211-5p inhibition attenuated the tumour growth and metastasis capacity of HepG2.2.15 cells in vivo. Collectively, lncRNA F11-AS1 acted as a modulator of miR-211-5p to positively regulate the expression of NR1I3, and the lncRNA F11-AS1/miR-211-5p/NR1I3 axis participated in HBV-related HCC progression via interference with the cellular physiology of HCC.
Collapse
Affiliation(s)
- Yibin Deng
- Clinic Medicine Research Center of Hepatobiliary Diseases, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China.,Department of Infectious Diseases, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China.,Centre for Medical Laboratory Science, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Zhongheng Wei
- Department of Oncology, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Meijin Huang
- Department of Infectious Diseases, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Guidan Xu
- Centre for Medical Laboratory Science, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Wujun Wei
- Centre for Medical Laboratory Science, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Bin Peng
- Centre for Medical Laboratory Science, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Shunqiang Nong
- Centre for Medical Laboratory Science, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| | - Houji Qin
- Department of Infectious Diseases, The Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China
| |
Collapse
|
|
20
|
Matsuyama H, Suzuki HI. Systems and Synthetic microRNA Biology: From Biogenesis to Disease Pathogenesis. Int J Mol Sci 2019; 21:E132. [PMID: 31878193 PMCID: PMC6981965 DOI: 10.3390/ijms21010132] [Citation(s) in RCA: 175] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 12/15/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs (miRNAs) are approximately 22-nucleotide-long, small non-coding RNAs that post-transcriptionally regulate gene expression. The biogenesis of miRNAs involves multiple steps, including the transcription of primary miRNAs (pri-miRNAs), nuclear Drosha-mediated processing, cytoplasmic Dicer-mediated processing, and loading onto Argonaute (Ago) proteins. Further, miRNAs control diverse biological and pathological processes via the silencing of target mRNAs. This review summarizes recent findings regarding the quantitative aspects of miRNA homeostasis, including Drosha-mediated pri-miRNA processing, Ago-mediated asymmetric miRNA strand selection, and modifications of miRNA pathway components, as well as the roles of RNA modifications (epitranscriptomics), epigenetics, transcription factor circuits, and super-enhancers in miRNA regulation. These recent advances have facilitated a system-level understanding of miRNA networks, as well as the improvement of RNAi performance for both gene-specific targeting and genome-wide screening. The comprehensive understanding and modeling of miRNA biogenesis and function have been applied to the design of synthetic gene circuits. In addition, the relationships between miRNA genes and super-enhancers provide the molecular basis for the highly biased cell type-specific expression patterns of miRNAs and the evolution of miRNA-target connections, while highlighting the importance of alterations of super-enhancer-associated miRNAs in a variety of human diseases.
Collapse
Affiliation(s)
- Hironori Matsuyama
- Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd., 1-11-1 Karasaki, Otsu-shi, Shiga 520-0106, Japan;
| | - Hiroshi I. Suzuki
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| |
Collapse
|
|
21
|
The Regulatory Role of MicroRNA in Hepatitis-B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) Pathogenesis. Cells 2019; 8:cells8121504. [PMID: 31771261 PMCID: PMC6953055 DOI: 10.3390/cells8121504] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) is an intractable public health problem in developing countries that is compounded by limited early detection and therapeutic options. Despite the early promise of utilizing the regulatory role of miRNA in liver cancer, this field remains largely in the work-in-progress phase. This exploratory review paper adopts a broad focus in order to collate evidence of the regulatory role of miRNA in each stage of the HBV-HCC continuum. This includes the regulatory role of miRNA in early HBV infection, chronic inflammation, fibrosis/cirrhosis, and the onset of HCC. The paper specifically investigates HBV dysregulated miRNA that influence the expression of the host/HBV genome in HBV-HCC pathogenesis and fully acknowledges that this does not cover the full spectrum of dysregulated miRNA. The sheer number of dysregulated miRNA in each phase support a hypothesis that future therapeutic interventions will need to consider incorporating multiple miRNA panels.
Collapse
|
|
22
|
LncRNAs with miRNAs in regulation of gastric, liver, and colorectal cancers: updates in recent years. Appl Microbiol Biotechnol 2019; 103:4649-4677. [PMID: 31062053 DOI: 10.1007/s00253-019-09837-5] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 04/07/2019] [Accepted: 04/08/2019] [Indexed: 12/15/2022]
Abstract
Long noncoding RNA (lncRNA) is a kind of RNAi molecule composed of hundreds to thousands of nucleotides. There are several major types of functional lncRNAs which participate in some important cellular pathways. LncRNA-RNA interaction controls mRNA translation and degradation or serves as a microRNA (miRNA) sponge for silencing. LncRNA-protein interaction regulates protein activity in transcriptional activation and silencing. LncRNA guide, decoy, and scaffold regulate transcription regulators of enhancer or repressor region of the coding genes for alteration of expression. LncRNA plays a role in cellular responses including the following activities: regulation of chromatin structural modification and gene expression for epigenetic and cell function control, promotion of hematopoiesis and maturation of immunity, cell programming in stem cell and somatic cell development, modulation of pathogen infection, switching glycolysis and lipid metabolism, and initiation of autoimmune diseases. LncRNA, together with miRNA, are considered the critical elements in cancer development. It has been demonstrated that tumorigenesis could be driven by homeostatic imbalance of lncRNA/miRNA/cancer regulatory factors resulting in biochemical and physiological alterations inside the cells. Cancer-driven lncRNAs with other cellular RNAs, epigenetic modulators, or protein effectors may change gene expression level and affect the viability, immortality, and motility of the cells that facilitate cancer cell cycle rearrangement, angiogenesis, proliferation, and metastasis. Molecular medicine will be the future trend for development. LncRNA/miRNA could be one of the potential candidates in this category. Continuous studies in lncRNA functional discrepancy between cancer cells and normal cells and regional and rational genetic differences of lncRNA profiles are critical for clinical research which is beneficial for clinical practice.
Collapse
|
|
23
|
Long non-coding RNA HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related hepatocellular carcinoma. Cancer Lett 2019; 454:158-170. [PMID: 30981758 DOI: 10.1016/j.canlet.2019.04.008] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 04/03/2019] [Accepted: 04/05/2019] [Indexed: 12/14/2022]
Abstract
Long noncoding RNA HULC is identified and highly expressed in hepatocellular carcinoma (HCC). Hepatitis B virus (HBV) is a key driver of liver cancer. In the present study, we found that HULC remarkably elevated the levels of HBeAg, HBsAg, HBcAg, pgRNA, HBx, HBV DNA and covalently closed circular DNA (cccDNA), which activated the HBV replication in HBV-expressing hepatoma cells or de novo HBV-infected cell lines (PHH, HepG2-NTCP and dHepaRG). Mechanistically, HULC enhanced HBV cccDNA stability by down-regulating the APOBEC3B in hepatoma cells. HULC significantly up-regulated microRNA-539, which targeted the 3'UTR of APOBEC3B mRNA. Luciferase reporter gene assays revealed a putative STAT3-binding site located in the upstream of miR-539 promoter. Moreover, we identified that HULC was able to elevate HBx, which co-activated the STAT3 to stimulate the miR-539 promoter. Then, miR-539 down-regulated APOBEC3B and promoted HBV replication. Functionally, HULC enhanced the growth of hepatoma cells by activating HBV in vitro and in vivo, which could be blocked by overexpressing APOBEC3B. In conclusion, HULC activates HBV by modulating HBx/STAT3/miR-539/APOBEC3B signaling in HBV-related HCC.
Collapse
|
|
24
|
Mao X, Tey SK, Ko FCF, Kwong EML, Gao Y, Ng IOL, Cheung ST, Guan XY, Yam JWP. C-terminal truncated HBx protein activates caveolin-1/LRP6/β-catenin/FRMD5 axis in promoting hepatocarcinogenesis. Cancer Lett 2019; 444:60-69. [DOI: 10.1016/j.canlet.2018.12.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 11/26/2018] [Accepted: 12/18/2018] [Indexed: 02/08/2023]
|
|
25
|
Abstract
Hepatocellular carcinoma (HCC) is associated with chronic inflammation and fibrosis arising from different etiologies, including hepatitis B and C and alcoholic and nonalcoholic fatty liver diseases. The inflammatory cytokines tumor necrosis factor-α and interleukin-6 and their downstream targets nuclear factor kappa B (NF-κB), c-Jun N-terminal kinase (JNK), and signal transducer and activator of transcription 3 drive inflammation-associated HCC. Further, while adaptive immunity promotes immune surveillance to eradicate early HCC, adaptive immune cells, such as CD8+ T cells, Th17 cells, and B cells, can also stimulate HCC development. Thus, the role of the hepatic immune system in HCC development is a highly complex topic. This review highlights the role of cytokine signals, NF-κB, JNK, innate and adaptive immunity, and hepatic stellate cells in HCC and discusses whether these pathways could be therapeutic targets. The authors will also discuss cholangiocarcinoma and liver metastasis because biliary inflammation and tumor-associated stroma are essential for cholangiocarcinoma development and because primary tumor-derived inflammatory mediators promote the formation of a "premetastasis niche" in the liver.
Collapse
Affiliation(s)
- Yoon Mee Yang
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - So Yeon Kim
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ekihiro Seki
- Division of Digestive and Liver Diseases, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| |
Collapse
|
|
26
|
Choi YM, Lee SY, Kim BJ. Naturally Occurring Hepatitis B Virus Mutations Leading to Endoplasmic Reticulum Stress and Their Contribution to the Progression of Hepatocellular Carcinoma. Int J Mol Sci 2019; 20:597. [PMID: 30704071 PMCID: PMC6387469 DOI: 10.3390/ijms20030597] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 01/23/2019] [Accepted: 01/24/2019] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global health problem that causes a wide range of pathological outcomes, including cirrhosis and hepatocellular carcinoma (HCC). Endoplasmic reticulum (ER) stress induction by HBV infection has been implicated in liver carcinogenesis and disease progression with chronic inflammation via enhanced inflammation, oxidative stress-mediated DNA damage, and hepatocyte proliferation. In the natural course of HBV infection, the accumulation of naturally occurring mutations in the HBV genome can generate several mutant types of HBV-encoded proteins, including three different proteins in the S ORF (SHBs, MHBs, and LHBs) and HBcAg in the C ORF, which could contribute to enhanced ER stress in infected hepatocytes mainly via increased ER accumulation of mutant proteins. However, it seems that there may be distinct capacity and pathway in ER stress-induction and distinct resulting clinical outcomes between HBV variants. In addition, the role of HBxAg mutations in ER stress remains unknown. However, it has been reported that HBxAg itself could exert ER stress in infected cells, resulting in HCC generation in chronic HBV patients. To date, review papers regarding ER stress-mediated HBV mutation have been limited into a specific mutation type: preS2 deletion. So, in this review, we will discuss details about various mutation types in all four regions of the HBV genome (preS1, preS2, S, and C) related to ER stress and their distinct ER stress mechanisms and clinical outcomes in terms of mutation types.
Collapse
Affiliation(s)
- Yu-Min Choi
- Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.
| | - So-Young Lee
- Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, Biomedical Sciences, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul 03080, Korea.
| |
Collapse
|
|
27
|
Wang B, Li W, Fang H, Zhou H. Hepatitis B virus infection is not associated with fatty liver disease: Evidence from a cohort study and functional analysis. Mol Med Rep 2018; 19:320-326. [PMID: 30387826 PMCID: PMC6297757 DOI: 10.3892/mmr.2018.9619] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 10/01/2018] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection has been reported to be associated with the prevalence of non-alcoholic fatty liver disease (NAFLD). However, the present study demonstrated that the incidence of fatty liver disease in HBV-infected subjects (16/152, 10.5%) was not significantly different from in non-HBV-infected subjects (292/1,714, 17%), following adjustment for age (odds ratio=0.656; 95% confidence interval=0.379–1.134; P=0.131). Hepatitis B protein X (HBx) is considered a key regulator in HBV infection and several studies have confirmed that HBx serves a pivotal role in the process of fatty liver disease. In the present study, it was demonstrated that HBx-expressing cells exhibited increased mitochondrial membrane potential, ATP generation, and endogenous mitochondrial respiration. In addition, higher levels of mitochondrial reactive oxygen species (ROS) were detected in HBx-expressing cells compared with in control cells. Increased ROS production may contribute to increased lipid droplet formation in HBx-expressing cells, whereas the removal of ROS with N-acetylcysteine may decrease the accumulation of lipid droplets in a time-dependent manner. In conclusion, the present findings indicated that HBV, and perhaps more specifically HBx, was not a protective factor against NAFLD. HBx may function as a risk factor for fatty liver disease, based on the findings of the present functional study; however, further studies are required to clarify the effects of HBx on hepatic steatosis.
Collapse
Affiliation(s)
- Bingqian Wang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Wenna Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Hezhi Fang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| | - Huaibin Zhou
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, College of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, P.R. China
| |
Collapse
|
|
28
|
Chang Z, Wang Y, Zhou X, Long JE. STAT3 roles in viral infection: antiviral or proviral? Future Virol 2018; 13:557-574. [PMID: 32201498 PMCID: PMC7079998 DOI: 10.2217/fvl-2018-0033] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Accepted: 05/14/2018] [Indexed: 02/06/2023]
Abstract
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which can be activated by cytokines, growth factor receptors, and nonreceptor-like tyrosine kinase. An activated STAT3 translocates into the nucleus and combines with DNA to regulate the expression of target genes involved in cell proliferation, differentiation, apoptosis and metastasis. Recent studies have shown that STAT3 plays important roles in viral infection and pathogenesis. STAT3 exhibits a proviral function in several viral infections, including those of HBV, HCV, HSV-1, varicella zoster virus, human CMV and measles virus. However, in some circumstances, STAT3 has an antiviral function in other viral infections, such as enterovirus 71, severe acute respiratory syndrome coronavirus and human metapneumovirus. This review summarizes the roles of STAT3 in viral infection and pathogenesis, and briefly discusses the molecular mechanisms involved in these processes.
Collapse
Affiliation(s)
- Zhangmei Chang
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Kunshan Center For Disease Control & Prevention, 458 Tongfengxi Road, Kunshan, Jiangsu, 215301, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Kunshan Center For Disease Control & Prevention, 458 Tongfengxi Road, Kunshan, Jiangsu, 215301, PR China
| | - Yan Wang
- Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China
| | - Xin Zhou
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China
| | - Jian-Er Long
- Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China.,Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College of Fudan University, Shanghai 200032, PR China.,Department of Medical Microbiology & Parasitology, Laboratory of Medical Microbiology, Shanghai Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China
| |
Collapse
|
|
29
|
Müller-Coan BG, Caetano BFR, Pagano JS, Elgui de Oliveira D. Cancer Progression Goes Viral: The Role of Oncoviruses in Aggressiveness of Malignancies. Trends Cancer 2018; 4:485-498. [DOI: 10.1016/j.trecan.2018.04.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 04/24/2018] [Accepted: 04/25/2018] [Indexed: 12/12/2022]
|
|
30
|
Non-coding RNAs in hepatocellular carcinoma: molecular functions and pathological implications. Nat Rev Gastroenterol Hepatol 2018; 15:137-151. [PMID: 29317776 DOI: 10.1038/nrgastro.2017.169] [Citation(s) in RCA: 340] [Impact Index Per Article: 48.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a leading lethal malignancy worldwide. However, the molecular mechanisms underlying liver carcinogenesis remain poorly understood. Over the past two decades, overwhelming evidence has demonstrated the regulatory roles of different classes of non-coding RNAs (ncRNAs) in liver carcinogenesis related to a number of aetiologies, including HBV, HCV and NAFLD. Among the ncRNAs, microRNAs, which belong to a distinct class of small ncRNAs, have been proven to play a crucial role in the post-transcriptional regulation of gene expression. Deregulation of microRNAs has been broadly implicated in the inactivation of tumour-suppressor genes and activation of oncogenes in HCC. Modern high-throughput sequencing analyses have unprecedentedly identified a very large number of non-coding transcripts. Divergent groups of long ncRNAs have been implicated in liver carcinogenesis through interactions with DNA, RNA or proteins. Overall, ncRNAs represent a burgeoning field of cancer research, and we are only beginning to understand the importance and complicity of the ncRNAs in liver carcinogenesis. In this Review, we summarize the common deregulation of small and long ncRNAs in human HCC. We also comprehensively review the pathological roles of ncRNAs in liver carcinogenesis, epithelial-to-mesenchymal transition and HCC metastasis and discuss the potential applications of ncRNAs as diagnostic tools and therapeutic targets in human HCC.
Collapse
|
|
31
|
C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties. Oncotarget 2018; 7:24005-17. [PMID: 27006468 PMCID: PMC5029680 DOI: 10.18632/oncotarget.8209] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Accepted: 03/02/2016] [Indexed: 12/12/2022] Open
Abstract
Tumor relapse after chemotherapy typifies hepatocellular carcinoma (HCC) and is believed to be attributable to residual cancer stem cells (CSCs) that survive initial treatment. Chronic infection with hepatitis B virus (HBV) has long been linked to the development of HCC. Upon infection, random HBV genome integration can lead to truncation of hepatitis B virus X (HBx) protein at the C-terminus. The resulting C-terminal-truncated HBx (HBx-ΔC) was previously shown to confer enhanced invasiveness and diminished apoptotic response in HCC cells. Here, we found HBx-ΔC to promote the appearance of a CD133 liver CSC subset and confer cancer and stem cell-like features in HCC. HBx-ΔC was exclusively detected in HCC cell lines that were raised from patients presented with a HBV background with concomitant CD133 expression. Stable overexpression of the naturally occurring HBx-ΔC mutants, HBx-Δ14 or HBx-Δ35, in HCC cells Huh7 and immortalized normal liver cells MIHA resulted in a significant increase in the cells ability to self-renew, resist chemotherapy and targeted therapy, migrate and induce angiogenesis. MIHA cells with the mutants stably overexpressed also resulted in the induction of CD133, mediated through STAT3 activation. RNA sequencing profiling of MIHA cells with or without HBx-ΔC mutants stably overexpressed identified altered FXR activation. This, together with rescue experiments using a selective FXR inhibitor suggested that C-terminal truncated HBx can mediate cancer stemness via FXR activation. Collectively, we find C-terminal truncated HBx mutants to confer cancer and stem cell-like features in vitro and to play an important role in driving tumor relapse in HCC.
Collapse
|
|
32
|
Dysregulation of cellular microRNAs by human oncogenic viruses - Implications for tumorigenesis. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS 2018; 1861:95-105. [PMID: 29378330 DOI: 10.1016/j.bbagrm.2018.01.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 01/15/2018] [Accepted: 01/21/2018] [Indexed: 12/11/2022]
Abstract
Infection with certain animal and human viruses, often referred to as tumor viruses, induces oncogenic processes in their host. These viruses can induce tumorigenesis through direct and/or indirect mechanisms, and the regulation of microRNAs expression has been shown to play a key role in this process. Some human oncogenic viruses can express their own microRNAs; however, they all can dysregulate the expression of cellular microRNAs, facilitating their respective life cycles. The modulation of cellular microRNAs expression brings consequences to the host cells that may lead to malignant transformation, since microRNAs regulate the expression of genes involved in oncogenic pathways. This review focus on the mechanisms used by each human oncogenic virus to dysregulate the expression of cellular microRNAs, and their impact on tumorigenesis.
Collapse
|
|
33
|
MicroRNA-Mediated Regulation of HMGB1 in Human Hepatocellular Carcinoma. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2754941. [PMID: 29651425 PMCID: PMC5832039 DOI: 10.1155/2018/2754941] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Accepted: 01/04/2018] [Indexed: 12/15/2022]
Abstract
High-mobility group box 1 (HMGB1) is a potential therapeutic target and novel biomarker in a variety of malignant tumors, including hepatocellular carcinoma (HCC). More recently, a number of microRNAs (miRNAs) are identified as a class of regulators for broad control of HMGB1-mediated biological actions in eukaryotic cells. In this review article we will describe representative miRNAs involved in regulating the HMGB1 signaling pathways in HCC cell lines and/or animal models. We also propose the possible mechanisms underlying the miRNA/HMGB1 axis and discuss the future clinical significance of miRNAs targeting HMGB1 molecule for HCC therapy.
Collapse
|
|
34
|
Wu J. Utilization of animal models to investigate nonalcoholic steatohepatitis-associated hepatocellular carcinoma. Oncotarget 2018; 7:42762-42776. [PMID: 27072576 PMCID: PMC5173170 DOI: 10.18632/oncotarget.8641] [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: 01/25/2016] [Accepted: 03/29/2016] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disorders with fat accumulation from simple fatty liver, nonalcoholic steatohepatitis (NASH), fibrosis/cirrhosis and NAFLD/NASH-associated hepatocellular carcinoma (HCC). NASH is a progressive form of NAFLD and requires medical attention. One of 5-10 NASH patients may progress to end-state liver disease (ESLD or cirrhosis) in 5-10 years; meanwhile, life-threatening complications of ESLD and HCC account for major mortality. An increasing burden of NAFLD in clinics, elucidation of its pathogenesis and progression, and assessment of the efficacy of potential therapeutics demand reliable animal models. Most NASH-associated HCC occurs in cirrhotic subjects; however, HCC does appear in NASH patients without cirrhosis. Lipotoxicity, oxidant stress, insulin resistance, endoplasmic reticulum stress, altered adipokine and lymphokine profiles and gut microbiome changes affect NAFLD progression and constitute key pathobiologic interplays. How these factors promote malignant transformation in a microenvironment of steatotic inflammation and fibrosis/cirrhosis, and lead to development of neoplasms is one of critical questions faced in the hepatology field. The present review summarizes the characteristics of emerging rodent NASH-HCC models, and discusses the challenges in utilizing these models to unveil the mysteries of NASH-associated HCC development.
Collapse
Affiliation(s)
- Jian Wu
- Key Laboratory of Molecular Virology, Fudan University Shanghai Medical College, Shanghai, China.,Shanghai Institute of Liver Diseases, Fudan University, Shanghai, China
| |
Collapse
|
|
35
|
C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway. Oncotarget 2017; 8:23507-23516. [PMID: 28186991 PMCID: PMC5410322 DOI: 10.18632/oncotarget.15183] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Accepted: 01/16/2017] [Indexed: 01/04/2023] Open
Abstract
Hepatitis B virus (HBV) is a major risk factor of chronic liver disease and hepatocellular carcinoma (HCC). Random integration of HBV DNA into the host genome is frequent in HCC leading to truncation of the HBV DNA, particularly at the C-terminal end of the HBV X protein (HBx). C-terminally truncated HBx (HBx-ΔC) has been implicated in playing a pro-oncogenic role in hepatocarcinogenesis. However, the mechanism whereby HBx-ΔC1 contributes to hepatocarcinogenesis remains unclear. In this study, we investigated the functional role of HBx-ΔC1 in regulating liver cancer stem cell (CSC) properties. Using Tet-on inducible system, we found that HBx-ΔC1 enhanced CSC properties including self-renewal, tumorigenicity, chemoresistance, migration and expression of liver CSC markers, when compared with the full-length HBx counterpart and vector control. Interestingly, HBx-ΔC1 conferred resistance in HCC cells towards sorafenib treatment through suppression of apoptotic cascade. In addition, HBx-ΔC1 upregulated a panel of stemness genes, in which Nanog was found to be among the most significant one in both trasnfected cell lines. Consistently, Nanog was upregulated in human HCC samples which had HBx-ΔC1 expression. Furthermore, the induction of CSC properties by HBx-ΔC1 was via the Stat3/Nanog pathway, as administration of Stat3 inhibitor abolished the HBx-ΔC1-induced self-renewing capacity. In conclusion, our data suggest that HBx-ΔC1 enhances liver CSCs properties through Stat3/Nanog cascade, and provide a new insight for the therapeutic intervention for HBV-related HCC.
Collapse
|
|
36
|
Hepatitis B Virus Activates Signal Transducer and Activator of Transcription 3 Supporting Hepatocyte Survival and Virus Replication. Cell Mol Gastroenterol Hepatol 2017; 4:339-363. [PMID: 28884137 PMCID: PMC5581872 DOI: 10.1016/j.jcmgh.2017.07.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2016] [Accepted: 07/13/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The human hepatitis B virus (HBV) is a major cause of chronic hepatitis and hepatocellular carcinoma, but molecular mechanisms driving liver disease and carcinogenesis are largely unknown. We therefore studied cellular pathways altered by HBV infection. METHODS We performed gene expression profiling of primary human hepatocytes infected with HBV and proved the results in HBV-replicating cell lines and human liver tissue using real-time polymerase chain reaction and Western blotting. Activation of signal transducer and activator of transcription (STAT3) was examined in HBV-replicating human hepatocytes, HBV-replicating mice, and liver tissue from HBV-infected individuals using Western blotting, STAT3-luciferase reporter assay, and immunohistochemistry. The consequences of STAT3 activation on HBV infection and cell survival were studied by chemical inhibition of STAT3 phosphorylation and small interfering RNA-mediated knockdown of STAT3. RESULTS Gene expression profiling of HBV-infected primary human hepatocytes detected no interferon response, while genes encoding for acute phase and antiapoptotic proteins were up-regulated. This gene regulation was confirmed in liver tissue samples of patients with chronic HBV infection and in HBV-related hepatocellular carcinoma. Pathway analysis revealed activation of STAT3 to be the major regulator. Interleukin-6-dependent and -independent activation of STAT3 was detected in HBV-replicating hepatocytes in cell culture and in vivo. Prevention of STAT3 activation by inhibition of Janus tyrosine kinases as well as small interfering RNA-mediated knockdown of STAT3-induced apoptosis and reduced HBV replication and gene expression. CONCLUSIONS HBV activates STAT3 signaling in hepatocytes to foster its own replication but also to prevent apoptosis of infected cells. This very likely supports HBV-related carcinogenesis.
Collapse
Key Words
- APR, acute phase response
- Apoptosis
- CRP, C-reactive protein
- DMSO, dimethyl sulfoxide
- FCS, fetal calf serum
- HBV pg RNA, hepatitis B pregenomic RNA
- HBV, Hepatitis B virus
- HBVtg, hepatitis B transgenic
- HBeAg, hepatitis B early antigen
- HCC, hepatocellular carcinoma
- HNF, hepatocyte nuclear factor
- Hepatitis B Virus Infection
- Hepatocellular Carcinoma
- IFN, interferon
- IL-6, interleukin 6
- IRF3, interferon regulatory factor 3
- NAC, N-acetyl-L-cysteine
- PCR, polymerase chain reaction
- PHH, primary human hepatocyte
- ROS, reactive oxygen species
- RT, reverse transcription
- STAT3 Signaling
- STAT3, signal transducer and activator of transcription 3
- cDNA, complementary DNA
- cRNA, complementary RNA
- cccDNA, covalently closed circular DNA
- mRNA, messenger RNA
- p.i., postinfection
- pSTAT3, phosphorylated signal transducer and activator of transcription 3
- pgRNA, pregenomic RNA
- siRNA, small interfering RNA
Collapse
|
|
37
|
Wang Z, Wu Z, Huang P. The function of miRNAs in hepatocarcinogenesis induced by hepatitis B virus X protein. Oncol Rep 2017. [DOI: 10.3892/or.2017.5716] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
|
|
38
|
Menahem B, Lubrano J, Duvoux C, Mulliri A, Alves A, Costentin C, Mallat A, Launoy G, Laurent A. Liver transplantation versus liver resection for hepatocellular carcinoma in intention to treat: An attempt to perform an ideal meta-analysis. Liver Transpl 2017; 23:836-844. [PMID: 28295992 DOI: 10.1002/lt.24758] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/17/2017] [Indexed: 12/14/2022]
Abstract
This meta-analysis compared the effects of liver transplantation (LT) and liver resection (LR) on overall survival (OS) and disease-free survival (DFS) in patients with hepatocellular carcinoma (HCC) small transplantable HCC or within Milan criteria. Articles comparing LR with LT for HCC, based on Milan criteria or small size, published up to June 2015 were selected, and a meta-analysis was performed. No randomized controlled trial has been published to date comparing survival outcomes in patients with HCC who underwent LR and LT. Nine studies were identified, including 570 patients who underwent LR and 861 who underwent LT. For HCC within the Milan criteria, the 1-year OS rates following LR and LT were 84.5% (473/560) and 84.4% (710/841), respectively (odds ratio [OR], 0.98; 95% confidence interval [CI], 0.71-1.33; P = 0.8), and the 5-year OS rates were 47.9% (273/570) and 59.3% (509/858), respectively (OR, 0.60; 95% CI, 0.35-1.02; P = 0.06). One-year DFS rates were similar (OR, 1.00; 95% CI, 0.39-2.61; P = 1.00), whereas the 3-year DFS rate was significantly lower in the LR group (54.4%, 210/386) than in the LT group (74.2%, 317/427; OR, 0.24; 95% CI, 0.07-0.80; P = 0.02), and the 5-year DFS rate was significantly lower for LR than LT (OR, 0.18; 95% CI, 0.06-0.53; P < 0.01). For small HCCs, the 5-year OS rate was significantly lower for patients who underwent LR than LT (OR, 0.30; 95% CI, 0.19-0.48; P < 0.001). In conclusion, relative to LR, LT in patients with HCC meeting the Milan criteria had no benefits before 10 years for OS. For DFS, the benefit is obtained after 3 years. Liver Transplantation 23 836-844 2017 AASLD.
Collapse
Affiliation(s)
- Benjamin Menahem
- Department of Digestive Surgery, University Hospital of Caen, Caen, France.,Normandie Université, UNICAEN, CEA, Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire Caen, INSERM Unités Mixtes de Recherche 1086, Centre François Baclesse, Caen, France
| | - Jean Lubrano
- Department of Digestive Surgery, University Hospital of Caen, Caen, France.,Normandie Université, UNICAEN, CEA, Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire Caen, INSERM Unités Mixtes de Recherche 1086, Centre François Baclesse, Caen, France
| | - Christophe Duvoux
- Department of Hepatology, University Hospital of Henri Mondor, Créteil, France
| | - Andrea Mulliri
- Department of Digestive Surgery, University Hospital of Caen, Caen, France
| | - Arnaud Alves
- Department of Digestive Surgery, University Hospital of Caen, Caen, France
| | - Charlotte Costentin
- Department of Hepatology, University Hospital of Henri Mondor, Créteil, France
| | - Ariane Mallat
- Department of Hepatology, University Hospital of Henri Mondor, Créteil, France
| | - Guy Launoy
- Normandie Université, UNICAEN, CEA, Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire Caen, INSERM Unités Mixtes de Recherche 1086, Centre François Baclesse, Caen, France
| | - Alexis Laurent
- Department of Hepatobiliary Surgery and Liver Transplantation, University Hospital of Henri Mondor, Créteil, France.,Unité INSERM U 1855, University Hospital of Henri Mondor, Créteil, France
| |
Collapse
|
|
39
|
Deng W, Zhang X, Ma Z, Lin Y, Lu M. MicroRNA-125b-5p mediates post-transcriptional regulation of hepatitis B virus replication via the LIN28B/let-7 axis. RNA Biol 2017; 14:1389-1398. [PMID: 28267418 DOI: 10.1080/15476286.2017.1293770] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/09/2023] Open
Abstract
MicroRNAs (miRNAs) are able to modulate hepatitis B virus (HBV) replication and play an important role in the pathogenesis of HBV infection. Recently, we have identified that serum miR-125b-5p levels correlated with HBV DNA levels and liver necroinflammation. In the present study, we addressed how miR-125b-5p regulated HBV replication at the different steps, inclduing viral transcription, assembly, and virion production and investigated the underlying mechanisms. We found that miR-125b-5p overexpression increased HBV replication without altering HBV transcription. This is the first demonstration of post-transcriptional miRNA regulation of HBV replication. In contrast, transfection of miR-125b-5p inhibitor resulted in downregulation of HBV replication in hepatoma cells. Further, miR-125b-5p inhibited the phosphorylation of retinoblastoma protein and blocked cell cycle progression at the G1/S phase in hepatoma cell lines. Our results indicate that certain miRNAs are able to arrest the cell cycle at G1 phase and may increase HBV replication. RNA sequencing revealed several liver-specific metabolic pathways regulated by miR-125b-5p, which was also found to suppress LIN28B and induce let-7 family members. Additional data demonstrated that miR-125b-5p targeted the LIN28B/let-7 axis to stimulate HBV replication at a post-transcriptional step.
Collapse
Affiliation(s)
- Wanyu Deng
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany.,b College of Life Science, Shangrao Normal University , Shangrao , China
| | - Xiaoyong Zhang
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Zhiyong Ma
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Yong Lin
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| | - Mengji Lu
- a Institute of Virology, University Hospital Essen, University of Duisburg-Essen , Essen , Germany
| |
Collapse
|
|
40
|
Zhang B, Han S, Feng B, Chu X, Chen L, Wang R. Hepatitis B virus X protein-mediated non-coding RNA aberrations in the development of human hepatocellular carcinoma. Exp Mol Med 2017; 49:e293. [PMID: 28186085 PMCID: PMC5336563 DOI: 10.1038/emm.2016.177] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Revised: 11/03/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has an important role in the development of human hepatocellular carcinoma (HCC). Accumulated evidence has shown that HBV-encoded X protein (HBx) can induce both genetic alterations in tumor suppressor genes and oncogenes, as well as epigenetic aberrations in HCC pathogens. Non-coding RNAs (ncRNAs) mainly include microRNAs and long non-coding RNAs (lncRNAs). Although ncRNAs cannot code proteins, growing evidence has shown that they have various important biological functions in cell proliferation, cell cycle control, anti-apoptosis, epithelial–mesenchymal transition, tumor invasion and metastasis. This review summarizes the current knowledge regarding the mechanisms and emerging roles of ncRNAs in the pathogenesis of HBV-related HCC. Accumulated data have shown that ncRNAs regulated by HBx have a crucial role in HBV-associated hepatocarcinogenesis. The findings of these studies will contribute to more clinical applications of HBV-related ncRNAs as potential diagnostic markers or as molecular therapeutic targets to prevent and treat HBV-related HCC.
Collapse
Affiliation(s)
- Bei Zhang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Siqi Han
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Bing Feng
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Xiaoyuan Chu
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Longbang Chen
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Rui Wang
- Department of Medical Oncology, Jinling Hospital, School of Medicine, Nanjing Medical University, Nanjing, Jiangsu, China
| |
Collapse
|
|
41
|
Pant K, Yadav AK, Gupta P, Rathore AS, Nayak B, Venugopal SK. Humic acid inhibits HBV-induced autophagosome formation and induces apoptosis in HBV-transfected Hep G2 cells. Sci Rep 2016; 6:34496. [PMID: 27708347 PMCID: PMC5052648 DOI: 10.1038/srep34496] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 09/14/2016] [Indexed: 12/26/2022] Open
Abstract
Hepatitis B Virus (HBV) utilizes several mechanisms to survive in the host cells and one of the main pathways being autophagosome formation. Humic acid (HA), one of the major components of Mineral pitch, is an Ayurvedic medicinal food, commonly used by the people of the Himalayan regions of Nepal and India for various body ailments. We hypothesized that HA could induce cell death and inhibit HBV-induced autophagy in hepatic cells. Incubation of Hep G2.2.1.5 cells (HepG2 cells stably expressing HBV) with HA (100 μM) inhibited both cell proliferation and autophagosome formation significantly, while apoptosis induction was enhanced. Western blot results showed that HA incubation resulted in decreased levels of beclin-1, SIRT-1 and c-myc, while caspase-3 and β-catenin expression were up-regulated. Western blot results showed that HA significantly inhibited the expression of HBx (3-fold with 50 μM and 5-fold with 100 μM) compared to control cells. When HA was incubated with HBx-transfected Hep G2 cells, HBx-induced autophagosome formation and beclin-1 levels were decreased. These data showed that HA induced apoptosis and inhibited HBV-induced autophagosome formation and proliferation in hepatoma cells.
Collapse
Affiliation(s)
- Kishor Pant
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India
| | - Ajay K. Yadav
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India
| | - Parul Gupta
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India
| | - Abhishek Singh Rathore
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Senthil K. Venugopal
- Faculty of Life Sciences and Biotechnology, South Asian University, Akbar Bhawan Chanakyapuri New Delhi, India
| |
Collapse
|
|
42
|
Liver Gene Expression Profiles Correlate with Virus Infection and Response to Interferon Therapy in Chronic Hepatitis B Patients. Sci Rep 2016; 6:31349. [PMID: 27546197 PMCID: PMC4992874 DOI: 10.1038/srep31349] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.
Collapse
|
|
43
|
Yin D, Wang Y, Sai W, Zhang L, Miao Y, Cao L, Zhai X, Feng X, Yang L. HBx-induced miR-21 suppresses cell apoptosis in hepatocellular carcinoma by targeting interleukin-12. Oncol Rep 2016; 36:2305-12. [PMID: 27571873 DOI: 10.3892/or.2016.5026] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 04/19/2016] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) plays a key role in the initiation and progression of HBV infection‑induced hepatocellular carcinoma (HCC). Oncogenic microRNA-21 (miR-21) can be modulated by HBx protein in HCC. However, critical regulator genes in the pathway of HBx-induced miR-21 in HCC remain unclear. This study aimed to investigate the role of HBx-induced miR-21 in the apoptosis of HCC cells. In the study, interleukin-12 (IL-12) was demonstrated as a direct target of miR-21 by dual‑luciferase report assay, and miR-21 was highly expressed in HCC cells (HepG2 and HepG2 2.2.15) compared to L02 cells, but IL-12 was weakly expressed as detected by real-time quantitative PCR (RT-qPCR). Furthermore, miR-21 mimics, inhibitor, HBx-targeted siRNA, and the HBx overexpression vector (pHBx) were used to observe the regulatory effects of HBx-induced miR-21 via IL-12, and cell apoptosis was assessed. The results showed that overexpression of HBx resulted in the inhibition of IL-12. A high level of miR-21 resulted in a significant increase in proliferation and a decrease in IL-12 expression. Inhibition of miR-21 resulted in a significant increase in apoptosis and increased IL-12 expression. The results suggest that HCC cell apoptosis was suppressed at least partially through HBx-induced miR-21 by targeting IL-12.
Collapse
Affiliation(s)
- Dian Yin
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Yilang Wang
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Wenli Sai
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, P.R. China
| | - Liang Zhang
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Yajun Miao
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Lili Cao
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Xiaolu Zhai
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Xiu Feng
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| | - Li Yang
- Department of Oncology, The First People's Hospital of Nantong, Nantong, Jiangsu 226001, P.R. China
| |
Collapse
|
|
44
|
Japanese Encephalitis Virus exploits the microRNA-432 to regulate the expression of Suppressor of Cytokine Signaling (SOCS) 5. Sci Rep 2016; 6:27685. [PMID: 27282499 PMCID: PMC4901348 DOI: 10.1038/srep27685] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 05/20/2016] [Indexed: 12/30/2022] Open
Abstract
Japanese encephalitis virus (JEV) is a plus strand RNA virus, which infects brain. MicroRNAs are regulatory non-coding RNAs which regulate the expression of various genes in cells. Viruses modulate the expression of various microRNAs to suppress anti-viral signaling and evade the immune response. SOCS (Suppressor of cytokine signalling) family of proteins are negative regulators of anti-viral Jak-STAT pathway. In this study, we demonstrated the regulatory role of SOCS5 in Jak-STAT signaling and its exploitation by JEV through a microRNA mediated mechanism. JEV infection in human brain microglial cells (CHME3) downregulated the expression of miR-432, and upregulated SOCS5 levels. SOCS5 was validated as a target of miR-432 by using 3'UTR clone of SOCS5 in luciferase vector along with miR-432 mimic. The overexpression of miR-432 prior to JEV infection enhanced the phosphorylation of STAT1 resulting into increased ISRE activity and cellular inflammatory response resulting into diminished viral replication. The knockdown of SOCS5 resulted into increased STAT1 phosphorylation and suppressed viral replication. JEV infection mediated downregulation of miR-432 leads to SOCS5 upregulation, which helps the virus to evade cellular anti-viral response. This study demonstrated that JEV utilizes this microRNA mediated strategy to manipulate cellular immune response promoting JEV pathogenesis.
Collapse
|
|
45
|
Zhu M, Lu Y, Li W, Guo J, Dong X, Lin B, Chen Y, Xie X, Li M. Hepatitis B Virus X Protein Driven Alpha Fetoprotein Expression to Promote Malignant Behaviors of Normal Liver Cells and Hepatoma Cells. J Cancer 2016; 7:935-946. [PMID: 27313784 PMCID: PMC4910586 DOI: 10.7150/jca.13628] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 03/15/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The infection of Hepatitis B virus (HBV) is closely associated with the development of hepatocellular carcinoma(HCC), HBV-X protein(HBx) is able to induce expression of alpha-fetoprotein(AFP) in normal liver cells, and AFP harbors a function to promote malignant transformation of normal liver cells, but the role AFP playing in malignant behaviors of HCC cells is still unclear. METHODS Fifty-six liver tissue samples were collected from the clinical patients through hepatectomy(include normal liver tissues, HBV-related hepatitis liver tissues and HBV-related HCC tissues), and diagnosis of these tissues by pathology section, expression of AFP, Ras and CXCR4 were evidenced by immunohisochemical staining and Western blotting; The proliferation of human normal liver cells line L-02 cells and human hepatoma cells line, HLE cells(non AFP-producing) were performed by MTT method; Repaired capacity of L-02 and HLE cells were compared by wound healing assay; Migration and invasion of these cells were analyzed by Transwell chamber assay; HBx expressed vectors(pcDNA3.1-HBx) were constructed and transfected into L-02 and HLE cells, effects of pcDNA3.1-HBx on the malignant behaviors were also detected by MTT, Transwell chamber assay and the expression of AFP, Ras and CXCR4 were evidenced by Western blotting. RESULTS we found that expression of AFP, Ras and CXCR4 in HBV-related HCC and lymph nodes metastasis tissues were significantly elevated compared with HBV-related HCC, non metastasis tissues and HBV-related hepatitis tissues; Expression of AFP, Ras and CXCR4 in HBV-related hepatitis tissues were significantly enhanced compared with normal liver tissues; The growth ratio, migratory and invasive ability, expression of AFP, Ras and CXCR4 of the cells were outstanding promoted while L-02 and HLE cells were transfected with pcDNA3.1-HBx vectors. The proliferation ratio, migration and invasion ability, and expression of Ras and CXCR4 were significantly inhibited while L-02-X and HLE-X cells(stably transfected with pcDNA3.1-HBx) were silenced AFP expression by AFP-siRNA. CONCLUSIONS HBx through stimulating expression of AFP to promote malignant behaviors of human normal liver cells and HCC cells; AFP maybe used as a novel biotarget for therapeutics of HCC patients.
Collapse
Affiliation(s)
- Mingyue Zhu
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Yan Lu
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Wei Li
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Junli Guo
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Xu Dong
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Bo Lin
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Yi Chen
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
| | - Xieju Xie
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 3. Department of Pathophysiology, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
| | - Mengsen Li
- 1. Hainan Provincial Key Laboratory of Carcinogenesis and Intervention, Hainan Medical College, Haikou 571199, Hainan Province, PR. China
- 2. Key Laboratory of Molecular Biology, Hainan Medical College, Haikou 571199, PR. China
- 4. Institution of Tumor, Hainan Medical College, Haikou 570102, Hainan Province, PR. China
| |
Collapse
|
|
46
|
Venturutti L, Romero LV, Urtreger AJ, Chervo MF, Cordo Russo RI, Mercogliano MF, Inurrigarro G, Pereyra MG, Proietti CJ, Izzo F, Díaz Flaqué MC, Sundblad V, Roa JC, Guzmán P, Bal de Kier Joffé ED, Charreau EH, Schillaci R, Elizalde PV. Stat3 regulates ErbB-2 expression and co-opts ErbB-2 nuclear function to induce miR-21 expression, PDCD4 downregulation and breast cancer metastasis. Oncogene 2016; 35:2208-22. [PMID: 26212010 DOI: 10.1038/onc.2015.281] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Revised: 06/15/2015] [Accepted: 06/18/2015] [Indexed: 02/07/2023]
Abstract
Membrane overexpression of the receptor tyrosine kinase ErbB-2 (MErbB-2) accounts for a clinically aggressive breast cancer (BC) subtype (ErbB-2-positive) with increased incidence of metastases. We and others demonstrated that nuclear ErbB-2 (NErbB-2) also plays a key role in BC and is a poor prognostic factor in ErbB-2-positive tumors. The signal transducer and activator of transcription 3 (Stat3), another player in BC, has been recognized as a downstream mediator of MErbB-2 action in BC metastasis. Here, we revealed an unanticipated novel direction of the ErbB-2 and Stat3 interaction underlying BC metastasis. We found that Stat3 binds to its response elements (GAS) at the ErbB-2 promoter to upregulate ErbB-2 transcription in metastatic, ErbB-2-positive BC. We validated these results in several BC subtypes displaying metastatic and non-metastatic ability, highlighting Stat3 general role as upstream regulator of ErbB-2 expression in BC. Moreover, we showed that Stat3 co-opts NErbB-2 function by recruiting ErbB-2 as its coactivator at the GAS sites in the promoter of microRNA-21 (miR-21), a metastasis-promoting microRNA (miRNA). Using an ErbB-2 nuclear localization domain mutant and a constitutively activated ErbB-2 variant, we found that NErbB-2 role as a Stat3 coactivator and also its direct role as transcription factor upregulate miR-21 in BC. This reveals a novel function of NErbB-2 as a regulator of miRNAs expression. Increased levels of miR-21, in turn, downregulate the expression of the metastasis-suppressor protein programmed cell death 4 (PDCD4), a validated miR-21 target. Using an in vivo model of metastatic ErbB-2-postive BC, in which we silenced Stat3 and reconstituted ErbB-2 or miR-21 expression, we showed that both are downstream mediators of Stat3-driven metastasis. Supporting the clinical relevance of our results, we found an inverse correlation between ErbB-2/Stat3 nuclear co-expression and PDCD4 expression in ErbB-2-positive primary invasive BCs. Our findings identify Stat3 and NErbB-2 as novel therapeutic targets to inhibit ErbB-2-positive BC metastasis.
Collapse
Affiliation(s)
- L Venturutti
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - L V Romero
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - A J Urtreger
- Research Area, Institute of Oncology 'Angel H. Roffo', University of Buenos Aires, Buenos Aires, Argentina
| | - M F Chervo
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - R I Cordo Russo
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - M F Mercogliano
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - G Inurrigarro
- Servicio de Patología, Sanatorio Mater Dei, Buenos Aires, Argentina
| | - M G Pereyra
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - C J Proietti
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - F Izzo
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - M C Díaz Flaqué
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - V Sundblad
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - J C Roa
- Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile
- Departamento de Anatomía Patológica, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
- Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Católica de Chile, Santiago de Chile, Chile
| | - P Guzmán
- Departamento de Anatomía Patológica (BIOREN), Universidad de La Frontera, Temuco, Chile
| | - E D Bal de Kier Joffé
- Research Area, Institute of Oncology 'Angel H. Roffo', University of Buenos Aires, Buenos Aires, Argentina
| | - E H Charreau
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - R Schillaci
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| | - P V Elizalde
- Laboratory of Molecular Mechanisms of Carcinogenesis, Instituto de Biología y Medicina Experimental, CONICET, Buenos Aires, Argentina
| |
Collapse
|
|
47
|
Han Li C, Chen Y. Small and Long Non-Coding RNAs: Novel Targets in Perspective Cancer Therapy. Curr Genomics 2016; 16:319-26. [PMID: 27047252 PMCID: PMC4763970 DOI: 10.2174/1389202916666150707155851] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/02/2015] [Accepted: 04/04/2015] [Indexed: 02/08/2023] Open
Abstract
Non-coding RNA refers to a large group of endogenous RNA molecules that have no protein coding capacity, while having specialized cellular and molecular functions. They possess wide range of functions such as the regulation of gene transcription and translation, post-transcriptional modification, epigenetic landscape establishment, protein scaffolding and cofactors recruitments. They are further divided into small non-coding RNAs with size < 200nt (e.g. miRNA, piRNA) and long non-coding RNAs with size >= 200nt (e.g. lincRNA, NAT). Increasing evidences suggest that both non-coding RNAs groups play important roles in cancer development, progression and pathology. Clinically, non-coding RNAs aberrations show high diagnostic and prognostic values. With improved understanding of the nature and roles of non-coding RNAs, it is believed that we can develop therapeutic treatment against cancer via the modulation of these RNA molecules. Advances in nucleic acid drug technology and computational simulation prompt the development of agents to intervene the malignant effects of non-coding RNAs. In this review, we will discuss the role of non-coding RNAs in cancer, and evaluate the potential of non-coding RNA-based cancer therapies.
Collapse
Affiliation(s)
- Chi Han Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yangchao Chen
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong;; Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China;; State Key Laboratory of Digestive Disease, Institute of Digestive Disease, The Chinese University of Hong Kong, Shatin, NT, Hong Kong
| |
Collapse
|
|
48
|
Bharti R, Dey G, Mandal M. Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement. Cancer Lett 2016; 375:51-61. [PMID: 26945971 DOI: 10.1016/j.canlet.2016.02.048] [Citation(s) in RCA: 186] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 02/24/2016] [Accepted: 02/24/2016] [Indexed: 12/12/2022]
Abstract
Interleukin-6 (IL-6) is a cytokine present in tumor microenvironment. Elevated level of IL-6 is associated with cancer cell proliferation, angiogenesis and metastasis through fueling STAT3, MAPK and Akt signaling. It promotes epithelial to mesenchymal transition (EMT) through altered expression of N-cadherin, vimentin, snail, twist and E-cadherin leading to cancer metastasis. IL-6 boosts mammosphere formation, self-renewal of stem cells, stemness properties of cancer cells and recruitment of mesenchymal stem cells. IL-6 is also a contributing factor for multidrug resistance in cancer due to gp130/MAPK/STAT3 mediated activation of transcription factors C/EBPβ/δ, overexpression of p-glycoprotein, EMT transition and expansion of stem cells. The in-depth investigation of IL-6 mediated cellular effects and its signaling pathway can provide the new window for future research and clinical development of IL-6 targeted therapy in cancer. Thus, an overview is delivered in this review deciphering the emerging aspect of the predominant influence of IL-6 in malignant transformation, EMT, cancer-associated stem cells and chemoresistance.
Collapse
Affiliation(s)
- Rashmi Bharti
- School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
| | - Goutam Dey
- School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India
| | - Mahitosh Mandal
- School of Medical Science & Technology, Indian Institute of Technology Kharagpur, Kharagpur 721302, West Bengal, India.
| |
Collapse
|
|
49
|
Lan T, Chang L, Wu L, Yuan YF. IL-6 Plays a Crucial Role in HBV Infection. J Clin Transl Hepatol 2015; 3:271-6. [PMID: 26807383 PMCID: PMC4721895 DOI: 10.14218/jcth.2015.00024] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 09/17/2015] [Accepted: 10/11/2015] [Indexed: 01/05/2023] Open
Abstract
Interleukin-6 (IL-6), a cytokine mainly produced by activated monocytes, has broad pleiotropic actions that affect the functions of a variety of lymphoid cells. The roles of IL-6 in regulating immunity to infections are currently being defined. Remarkably, IL-6-mediated cellular and humoral immune responses play a crucial role in determining the outcome of viral infection. This article reviews the current knowledge on the critical role of IL-6 in hepatitis B virus (HBV) infection. As a competent intermediary, IL-6 derived from activated monocytes plays an important role in promoting lymphocytes responses that are essential for effective viral control. However, as a mediator of inflammation, IL-6 is also involved in the development of HBV-induced liver cirrhosis and exacerbating liver injury. Overall, the current data point to IL-6 as an immunoregulatory cytokine in HBV infection. Immunotherapeutic strategies aimed at optimizing the beneficial effects of IL-6 in HBV infection may prove to be an ordeal in the future, as they should foster the strengths of IL-6 while circumventing potential drawbacks.
Collapse
Affiliation(s)
- Tian Lan
- Zhongnan Hospital of Wuhan University, Department of Hepatobiliary Surgery, Wuhan University, Wuhan, China
| | - Lei Chang
- Zhongnan Hospital of Wuhan University, Department of Hepatobiliary Surgery, Wuhan University, Wuhan, China
| | - Long Wu
- Zhongnan Hospital of Wuhan University, Department of Hepatobiliary Surgery, Wuhan University, Wuhan, China
| | - Yu-Feng Yuan
- Zhongnan Hospital of Wuhan University, Department of Hepatobiliary Surgery, Wuhan University, Wuhan, China
- Correspondence to: Yu-Feng Yuan, Zhongnan Hospital of Wuhan University, Department of Hepatobiliary Surgery, Wuhan University, Wuhan 430071, Hubei, China. Tel: +86-027-67812888, Fax: +86-027-67812892, E-mail:
| |
Collapse
|
|
50
|
Lu JW, Ho YJ, Yang YJ, Liao HA, Ciou SC, Lin LI, Ou DL. Zebrafish as a disease model for studying human hepatocellular carcinoma. World J Gastroenterol 2015; 21:12042-12058. [PMID: 26576090 PMCID: PMC4641123 DOI: 10.3748/wjg.v21.i42.12042] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Revised: 05/28/2015] [Accepted: 08/31/2015] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is one of the world’s most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury.
Collapse
|