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1
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Akade E, Jalilian S. The role of high mobility group AT-hook 1 in viral infections: Implications for cancer pathogenesis. Int J Biochem Cell Biol 2024; 169:106532. [PMID: 38278412 DOI: 10.1016/j.biocel.2024.106532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 11/25/2023] [Accepted: 01/18/2024] [Indexed: 01/28/2024]
Abstract
The crucial role of high mobility group AT-hook 1 (HMGA1) proteins in nuclear processes such as gene transcription, DNA replication, and chromatin remodeling is undeniable. Elevated levels of HMGA1 have been associated with unfavorable clinical outcomes and adverse differentiation status across various cancer types. HMGA1 regulates a diverse array of biological pathways, including tumor necrosis factor-alpha/nuclear factor-kappa B (TNF-α/NF-κB), epidermal growth factor receptor (EGFR), Hippo, Rat sarcoma/extracellular signal-regulated kinase (Ras/ERK), protein kinase B (Akt), wingless-related integration site/beta-catenin (Wnt/beta-catenin), and phosphoinositide 3-kinase/protein kinase B (PI3-K/Akt). While researchers have extensively investigated tumors in the reproductive, digestive, urinary, and hematopoietic systems, mounting evidence suggests that HMGA1 plays a critical role as a tumorigenic factor in tumors across all functional systems. Given its broad interaction network, HMGA1 is an attractive target for viral manipulation. Some viruses, including herpes simplex virus type 1, human herpesvirus 8, human papillomavirus, JC virus, hepatitis B virus, human immunodeficiency virus type 1, severe acute respiratory syndrome Coronavirus 2, and influenza viruses, utilize HMGA1 influence for infection. This interaction, particularly in oncogenesis, is crucial. Apart from the direct oncogenic effect of some of the mentioned viruses, the hit-and-run theory postulates that viruses can instigate cancer even before being completely eradicated from the host cell, implying a potentially greater impact of viruses on cancer development than previously assumed. This review explores the interplay between HMGA1, viruses, and host cellular machinery, aiming to contribute to a deeper understanding of viral-induced oncogenesis, paving the way for innovative strategies in cancer research and treatment.
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Affiliation(s)
- Esma'il Akade
- Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Shahram Jalilian
- Department of Medical Virology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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2
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Zhang MH, Yuan YF, Liu LJ, Wei YX, Yin WY, Zheng LZY, Tang YY, Lv Z, Zhu F. Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:4706-4735. [PMID: 37664153 PMCID: PMC10473924 DOI: 10.3748/wjg.v29.i31.4706] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/29/2023] [Accepted: 08/01/2023] [Indexed: 08/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.
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Affiliation(s)
- Ming-He Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Feng Yuan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Li-Juan Liu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yu-Xin Wei
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Wan-Yue Yin
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Lan-Zhuo-Yin Zheng
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Ying-Ying Tang
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Department of Neurology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Zhao Lv
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Fan Zhu
- State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
- Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, Hubei Province, China
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3
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Cao X, Chen H, Li Z, Li X, Yang X, Jin Q, Liang Y, Zhang J, Zhou M, Zhang N, Chen G, Du H, Zao X, Ye Y. Network pharmacology and in vitro experiments-based strategy to investigate the mechanisms of KangXianYiAi formula for hepatitis B virus-related hepatocellular carcinoma. Front Pharmacol 2022; 13:985084. [PMID: 36133813 PMCID: PMC9483169 DOI: 10.3389/fphar.2022.985084] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
The Chinese traditional medicine KangXianYiAi formula (KXYA) is used to treat hepatic disease in the clinic. Here we aim to confirm the therapeutic effects and explore the pharmacological mechanisms of KXYA on hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We first collected and analyzed clinical data of 40 chronic hepatitis B (CHB) patients with precancerous liver lesions under KXYA treatment. Then, the cell viability, migration, cell cycle, and apoptosis of HepAD38 cells with KXYA treatment were examined. Next, we performed network pharmacological analysis based on database mining to obtain the key target pathways and genes of KXYA treatment on HBV-related HCC. We finally analyzed the expression of the key genes between normal and HBV-related HCC tissues in databases and measured the mRNA expression of the key genes in HepAD38 cells after KXYA treatment. The KXYA treatment could reduce the liver nodule size of CHB patients, suppress the proliferation and migration capabilities, and promote apoptosis of HepAD38 cells. The key pathways of KXYA on HBV-related HCC were Cancer, Hepatitis B, Viral carcinogenesis, Focal adhesion, and PI3K-Akt signaling, and KXYA treatment could regulate the expression of the key genes including HNF4A, MAPK8, NR3C1, PTEN, EGFR, and HDAC1. The KXYA exhibited a curative effect via inhibiting proliferation, migration, and promoting apoptosis of HBV-related HCC and the pharmacological mechanism was related to the regulation of the expression of HNF4A, MAPK8, NR3C1, PTEN, EGFR, and HDAC1.
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Affiliation(s)
- Xu Cao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Hening Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Zhiguo Li
- Beijing Fengtai Hospital of Integrated Traditional and Western Medicine, Beijing, China
| | - Xiaoke Li
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Xianzhao Yang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Qiushuo Jin
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yijun Liang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Jiaxin Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
| | - Meiyue Zhou
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Ningyi Zhang
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Guang Chen
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Hongbo Du
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Xiaobin Zao
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
| | - Yong’an Ye
- Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, China
- Institute of Liver Diseases, Beijing University of Chinese Medicine, Beijing, China
- *Correspondence: Guang Chen, ; Hongbo Du, ; Xiaobin Zao, ; Yong’an Ye,
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ROS-Related miRNAs Regulate Immune Response and Chemoradiotherapy Sensitivity in Hepatocellular Carcinoma by Comprehensive Analysis and Experiment. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:4713518. [PMID: 35585886 PMCID: PMC9110211 DOI: 10.1155/2022/4713518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 04/09/2022] [Indexed: 11/28/2022]
Abstract
Reactive oxygen species (ROS) plays an essential role in the development of cancer. Here, we chose ROS-related miRNAs for consensus clustering analysis and ROS score construction. We find that ROS is extremely associated with prognosis, tumor immune microenvironment (TIME), gene mutations, N6-methyladenosine (m6A) methylation, and chemotherapy sensitivity in hepatocellular carcinoma (HCC). Mechanistically, ROS may affect the prognosis of HCC patients in numerous ways. Moreover, miR-210-3p and miR-106a-5p significantly increased the ROS level and stagnated cell cycle at G2/M in HCC; the results were more obvious in cells after ionizing radiation (IR). Finally, the two miRNAs suppressed cell proliferation, migration, and invasion and promoted apoptosis in huh7 and smmc7721 cells. It indicated that ROS might affect the prognosis of HCC patients through immune response and increase the sensitivity of HCC patients to radiotherapy and chemotherapy.
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Letafati A, Najafi S, Mottahedi M, Karimzadeh M, Shahini A, Garousi S, Abbasi-Kolli M, Sadri Nahand J, Tamehri Zadeh SS, Hamblin MR, Rahimian N, Taghizadieh M, Mirzaei H. MicroRNA let-7 and viral infections: focus on mechanisms of action. Cell Mol Biol Lett 2022; 27:14. [PMID: 35164678 PMCID: PMC8853298 DOI: 10.1186/s11658-022-00317-9] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/26/2022] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs (miRNAs) are fundamental post-transcriptional modulators of several critical cellular processes, a number of which are involved in host defense mechanisms. In particular, miRNA let-7 functions as an essential regulator of the function and differentiation of both innate and adaptive immune cells. Let-7 is involved in several human diseases, including cancer and viral infections. Several viral infections have found ways to dysregulate the expression of miRNAs. Extracellular vesicles (EV) are membrane-bound lipid structures released from many types of human cells that can transport proteins, lipids, mRNAs, and miRNAs, including let-7. After their release, EVs are taken up by the recipient cells and their contents released into the cytoplasm. Let-7-loaded EVs have been suggested to affect cellular pathways and biological targets in the recipient cells, and can modulate viral replication, the host antiviral response, and the action of cancer-related viruses. In the present review, we summarize the available knowledge concerning the expression of let-7 family members, functions, target genes, and mechanistic involvement in viral pathogenesis and host defense. This may provide insight into the development of new therapeutic strategies to manage viral infections.
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Affiliation(s)
- Arash Letafati
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sajad Najafi
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehran Mottahedi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Karimzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahini
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Setareh Garousi
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Javid Sadri Nahand
- Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Michael R. Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028 South Africa
| | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran
- Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghizadieh
- Department of Pathology, School of Medicine, Center for Women’s Health Research Zahra, Tabriz University of Medical Sciences, Tabriz, Islamic Republic of Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
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6
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Philips CA, Ahamed R, Abduljaleel JK, Rajesh S, Augustine P. Critical Updates on Chronic Hepatitis B Virus Infection in 2021. Cureus 2021; 13:e19152. [PMID: 34733599 PMCID: PMC8557099 DOI: 10.7759/cureus.19152] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a global healthcare burden in the form of chronic liver disease, cirrhosis, liver failure and liver cancer. There is no definite cure for the virus and even though extensive vaccination programs have reduced the burden of liver disease in the future population, treatment options to eradicate the virus from the host are still lacking. In this review, we discuss in detail current updates on the structure and applied biology of the virus in the host, examine updates to current treatment and explore novel and state-of-the-art therapeutics in the pipeline for management of chronic HBV. Furthermore, we also specifically review clinical updates on HBV-related acute on chronic liver failure (ACLF). Current treatments for chronic HBV infection have seen important updates in the form of considerations for treating patients in the immune tolerant phase and some clarity on end points for treatment and decisions on finite therapy with nucleos(t)ide inhibitors. Ongoing cutting-edge research on HBV biology has helped us identify novel target areas in the life cycle of the virus for application of new therapeutics. Due to improvements in the area of genomics, the hope for therapeutic vaccines, vector-based treatments and focused management aimed at targeting host integration of the virus and thereby a total cure could become a reality in the near future. Newer clinical prognostic tools have improved our understanding of timing of specific treatment options for the catastrophic syndrome of ACLF secondary to reactivation of HBV. In this review, we discuss in detail pertinent updates regarding virus biology and novel therapeutic targets with special focus on the appraisal of prognostic scores and treatment options in HBV-related ACLF.
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Affiliation(s)
- Cyriac A Philips
- Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, IND
| | - Rizwan Ahamed
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Jinsha K Abduljaleel
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Sasidharan Rajesh
- Diagnostic and Interventional Radiology, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
| | - Philip Augustine
- Gastroenterology and Advanced Gastrointestinal Endoscopy, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, IND
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7
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Ghosh S, Chakraborty A, Banerjee S. Persistence of Hepatitis B Virus Infection: A Multi-Faceted Player for Hepatocarcinogenesis. Front Microbiol 2021; 12:678537. [PMID: 34526974 PMCID: PMC8435854 DOI: 10.3389/fmicb.2021.678537] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 07/06/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection has a multi-dimensional effect on the host, which not only alters the dynamics of immune response but also persists in the hepatocytes to predispose oncogenic factors. The virus exists in multiple forms of which the nuclear localized covalently closed circular DNA (cccDNA) is the most stable and the primary reason for viral persistence even after clearance of surface antigen and viral DNA. The second reason is the existence of pregenomic RNA (pgRNA) containing virion particles. On the other hand, the integration of the viral genome in the host chromosome also leads to persistent production of viral proteins along with the chromosomal instabilities. The interferon treatment or administration of nucleot(s)ide analogs leads to reduction in the viral DNA load, but the pgRNA and surface antigen clearance are a slow process and complete loss of serological HBsAg is rare. The prolonged exposure of immune cells to the viral antigens, particularly HBs antigen, in the blood circulation results in T-cell exhaustion, which disrupts immune clearance of the virus and virus-infected cells. In addition, it predisposes immune-tolerant microenvironment, which facilitates the tumor progression. Thus cccDNA, pgRNA, and HBsAg along with the viral DNA could be the therapeutic targets in the early disease stages that may improve the quality of life of chronic hepatitis B patients by impeding the progression of the disease toward hepatocellular carcinoma.
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Affiliation(s)
| | | | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
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8
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Immunopathogenesis of HBV Infection. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1179:71-107. [DOI: 10.1007/978-981-13-9151-4_4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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9
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Wu Y, Wen J, Xiao W, Zhang B. Pregenomic RNA: How to assist the management of chronic hepatitis B? Rev Med Virol 2019; 29:e2051. [PMID: 31074177 DOI: 10.1002/rmv.2051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/31/2019] [Accepted: 04/01/2019] [Indexed: 12/17/2022]
Abstract
Pregenomic RNA (pgRNA) is an emerging serological marker for chronic hepatitis B virus (HBV) infection. While pgRNA is principally the template for viral proteins and viral DNAs, additional novel functions for the serum pgRNA have recently been described. These results extend for pgRNA a regulatory function in the viral life cycle and potentially a role in pathogenesis. Here, we review the diverse roles of pgRNA in HBV replication and pathogenesis, emphasizing how the unique structure of this RNA is key to its various functions. We focus in particular on the role of HBV pgRNA in guiding antiviral therapy including nucleot(s)ide analog interruption and role as a marker of cure with new curative therapies. We also briefly allude to the emerging niche for new direct-acting or indirect-acting antivirals targeting pgRNA.
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Affiliation(s)
- Yongbin Wu
- Department of Laboratory Medicine, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Jian Wen
- Department of Hematology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin, China
| | - Weiwei Xiao
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
| | - Bao Zhang
- Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, China
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10
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Li X, Xu Y, Ding Y, Li C, Zhao H, Wang J, Meng S. Posttranscriptional upregulation of HER3 by HER2 mRNA induces trastuzumab resistance in breast cancer. Mol Cancer 2018; 17:113. [PMID: 30068375 PMCID: PMC6090962 DOI: 10.1186/s12943-018-0862-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 07/24/2018] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND HER2 gene amplification generates an enormous number of HER2 transcripts, but the global effects on endogenous miRNA targets including HER family members in breast cancer are unexplored. METHODS We generated a HER2-3'UTR expressing vector to test the tumor-promoting properties in HER2 low expressing T47D and MCF7 cells. Through microarray analysis and real-time PCR analysis we identified genes that were regulated by HER2-3'UTR. Positive and negative manipulation of miRNA expression, response element mutational studies and transcript reporter assays were performed to explore the mechanism of competitive sequestration of miR125a/miRNA125b by HER2 3'UTR. To investigate if trastuzumab-induced upregulation of HER3 is also mediated through miRNA de-repression, we used the CRISPR/cas9 to mutate the endogenous HER2 mRNA in HER2 over-expressing Au565 cells. Finally, we looked at cohorts of breast cancer samples of our own and the TCGA to show if HER2 and HER3 mRNAs correlate with each other. RESULTS The HER2 3'UTR pronouncedly promoted cell proliferation, colony formation, and breast tumor growth. High-throughput sequencing revealed a significant increase in HER3 mRNA and protein levels by the HER2 3'untranslated region (3'UTR). The HER2 3'UTR harboring a shared miR-125a/b response element induced miR-125a/b sequestration and thus resulted in HER3 mRNA derepression. Trastuzumab treatment upregulated HER3 via elevated HER2 mRNA expression, leading to trastuzumab resistance. Depletion of miR-125a/b enhanced the antitumor activity of trastuzumab. Microarray data from HER2-overexpressing primary breast cancer showed significant elevation of mRNAs for predicted miR-125a/b targets compared to non-targets. CONCLUSIONS These results suggest that HER2 3'UTR-mediated HER3 upregulation is involved in breast cell transformation, increased tumor growth, and resistance to anti-HER2 therapy. The combinatorial targeting of HER3 mRNA or miR-125a/b may offer an effective tool for breast cancer therapy.
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Affiliation(s)
- Xin Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People's Republic of China.
| | - Yuxiu Xu
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People's Republic of China.
| | - Yun Ding
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People's Republic of China
| | - Changfei Li
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People's Republic of China
| | - Hong Zhao
- Cancer Institute and Hospital, Chinese Academy of Medical Sciences, Beijing, People's Republic of China
| | - Jiandong Wang
- The General Hospital of People's Liberation Army, Beijing, People's Republic of China
| | - Songdong Meng
- CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, People's Republic of China. .,University of Chinese Academy of Sciences, Beijing, People's Republic of China.
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11
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Hong M, Sun H, Xu L, Yue Q, Shen G, Li M, Tang B, Li CZ. In situ monitoring of cytoplasmic precursor and mature microRNA using gold nanoparticle and graphene oxide composite probes. Anal Chim Acta 2018; 1021:129-139. [DOI: 10.1016/j.aca.2018.03.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 03/07/2018] [Accepted: 03/09/2018] [Indexed: 01/12/2023]
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12
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Nie X, Liu Y, Chen WD, Wang YD. Interplay of miRNAs and Canonical Wnt Signaling Pathway in Hepatocellular Carcinoma. Front Pharmacol 2018; 9:657. [PMID: 29977206 PMCID: PMC6021530 DOI: 10.3389/fphar.2018.00657] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 06/01/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma is one of the leading causes of cancer death worldwide and the activation of canonical Wnt signaling pathway is universal in hepatocellular carcinoma patients. MicroRNAs are found to participate in the pathogenesis of hepatocellular carcinoma by activating or inhibiting components in the canonical Wnt signaling pathway. Meanwhile, transcriptional activation of microRNAs by canonical Wnt signaling pathway also contributes to the occurrence and progression of hepatocellular carcinoma. Pharmacological inhibition of hepatocellular carcinoma pathogenesis and other cancers by microRNAs are now in clinical trials despite the challenges of identifying efficient microRNAs candidates and safe delivery vehicles. The focus of this review is on the interplay mechanisms between microRNAs and canonical Wnt signaling pathway in hepatocellular carcinoma, and a deep understanding of the crosstalk will promote to develop a better management of this disease.
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Affiliation(s)
- Xiaobo Nie
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China
| | - Yiran Liu
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Department of Pathology, Henan Provincial People's Hospital, Zhengzhou, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, School of Medicine, Henan University, Kaifeng, China.,Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University, Hohhot, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
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13
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Sekiba K, Otsuka M, Ohno M, Yamagami M, Kishikawa T, Suzuki T, Ishibashi R, Seimiya T, Tanaka E, Koike K. Hepatitis B virus pathogenesis: Fresh insights into hepatitis B virus RNA. World J Gastroenterol 2018; 24:2261-2268. [PMID: 29881235 PMCID: PMC5989240 DOI: 10.3748/wjg.v24.i21.2261] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 04/24/2018] [Accepted: 04/26/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is still a worldwide health concern. While divergent factors are involved in its pathogenesis, it is now clear that HBV RNAs, principally templates for viral proteins and viral DNAs, have diverse biological functions involved in HBV pathogenesis. These functions include viral replication, hepatic fibrosis and hepatocarcinogenesis. Depending on the sequence similarities, HBV RNAs may act as sponges for host miRNAs and may deregulate miRNA functions, possibly leading to pathological consequences. Some parts of the HBV RNA molecule may function as viral-derived miRNA, which regulates viral replication. HBV DNA can integrate into the host genomic DNA and produce novel viral-host fusion RNA, which may have pathological functions. To date, elimination of HBV-derived covalently closed circular DNA has not been achieved. However, RNA transcription silencing may be an alternative practical approach to treat HBV-induced pathogenesis. A full understanding of HBV RNA transcription and the biological functions of HBV RNA may open a new avenue for the development of novel HBV therapeutics.
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Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Mari Yamagami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Eri Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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14
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Classification of heterogeneous genetic variations of microRNA regulome in cancer. Cancer Lett 2018; 419:128-138. [DOI: 10.1016/j.canlet.2018.01.043] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/30/2017] [Accepted: 01/09/2018] [Indexed: 12/12/2022]
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15
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Abstract
High-risk human papillomavirus infection is essential for the malignant transformation of cervical cancer and can inhibit host miR-27a expression. We investigated the role and mechanism of miR-27a in cervical cancer progression. miR-27a is decreased in cervical cancer cell lines and miR-27a-agomir inhibited the cell proliferation, migration, and invasion properties of HeLa (adenocarcinoma) cells, but not in SiHa cells (squamous cell carcinoma). Luciferase assays revealed that miR-27a directly targets the 3′-UTR of transforming growth factor beta receptor I (TGF-βRI) and downregulates TGF-β signaling. The co-transfection of a TGF-βRI expression vector largely restored the inhibition of TGF-β signaling, cell proliferation, migration, and invasion mediated by miR-27a-agomir. Also, miR-27a-agomir slows down the growth of subcutaneous HeLa xenografts and downregulates the TGF-βRI expression and TGF-β signaling in tumor in vivo. Tissue microarray analysis revealed a low miR-27a level in adenocarcinoma cells, but not in squamous cell carcinoma cells, which was negatively associated with TGF-βRI expression. High TGF-βRI correlated with deep stromal invasion and lymph node metastasis. These results suggest that miR-27a acts as a tumor suppressor in cervical cancer, especially in adenocarcinoma, by inhibiting TGF-βRI signaling pathway. Thus, enhancing miR-27a expression and function may be a novel treatment strategy for cervical adenocarcinoma.
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16
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Lai YC, Ushio N, Rahman MM, Katanoda Y, Ogihara K, Naya Y, Moriyama A, Iwanaga T, Saitoh Y, Sogawa T, Sunaga T, Momoi Y, Izumi H, Miyoshi N, Endo Y, Fujiki M, Kawaguchi H, Miura N. Aberrant expression of microRNAs and the miR-1/MET pathway in canine hepatocellular carcinoma. Vet Comp Oncol 2018; 16:288-296. [DOI: 10.1111/vco.12379] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2017] [Revised: 11/16/2017] [Accepted: 11/30/2017] [Indexed: 12/15/2022]
Affiliation(s)
- Y.-C. Lai
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
- The United Graduate School of Veterinary Science; Yamaguchi University; Yamaguchi Japan
| | - N. Ushio
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
- The United Graduate School of Veterinary Science; Yamaguchi University; Yamaguchi Japan
| | - M. M. Rahman
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
- The United Graduate School of Veterinary Science; Yamaguchi University; Yamaguchi Japan
| | - Y. Katanoda
- Laboratory of Veterinary Diagnostic Imaging, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - K. Ogihara
- Laboratory of Pathology, School of Life and Environmental Science; Azabu University; Sagamihara Japan
| | - Y. Naya
- Laboratory of Pathology, School of Life and Environmental Science; Azabu University; Sagamihara Japan
| | - A. Moriyama
- Drug Safety Research Laboratories; Shin Nippon Biomedical Laboratories, Ltd.; Kagoshima Japan
| | - T. Iwanaga
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - Y. Saitoh
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - T. Sogawa
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - T. Sunaga
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - Y. Momoi
- Laboratory of Veterinary Diagnostic Imaging, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - H. Izumi
- Drug Safety Research Laboratories; Shin Nippon Biomedical Laboratories, Ltd.; Kagoshima Japan
| | - N. Miyoshi
- Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - Y. Endo
- Laboratory of Small Animal Internal Medicine, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - M. Fujiki
- Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
| | - H. Kawaguchi
- Department of Hygiene and Health Promotion Medicine; Kagoshima University Graduate School of Medical and Dental Sciences; Kagoshima Japan
| | - N. Miura
- Veterinary Teaching Hospital, Joint Faculty of Veterinary Medicine; Kagoshima University; Kagoshima Japan
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17
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Drury RE, O'Connor D, Pollard AJ. The Clinical Application of MicroRNAs in Infectious Disease. Front Immunol 2017; 8:1182. [PMID: 28993774 PMCID: PMC5622146 DOI: 10.3389/fimmu.2017.01182] [Citation(s) in RCA: 121] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/06/2017] [Indexed: 12/19/2022] Open
Abstract
MicroRNAs (miRNAs) are short single-stranded non-coding RNA sequences that posttranscriptionally regulate up to 60% of protein encoding genes. Evidence is emerging that miRNAs are key mediators of the host response to infection, predominantly by regulating proteins involved in innate and adaptive immune pathways. miRNAs can govern the cellular tropism of some viruses, are implicated in the resistance of some individuals to infections like HIV, and are associated with impaired vaccine response in older people. Not surprisingly, pathogens have evolved ways to undermine the effects of miRNAs on immunity. Recognition of this has led to new experimental treatments, RG-101 and Miravirsen—hepatitis C treatments which target host miRNA. miRNAs are being investigated as novel infection biomarkers, and they are being used to design attenuated vaccines, e.g., against Dengue virus. This comprehensive review synthesizes current knowledge of miRNA in host response to infection with emphasis on potential clinical applications, along with an evaluation of the challenges still to be overcome.
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Affiliation(s)
- Ruth E Drury
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
| | - Daniel O'Connor
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
| | - Andrew J Pollard
- Oxford Vaccine Group, Centre for Clinical Vaccinology and Tropical Medicine, Department of Paediatrics, University of Oxford, The Churchill Hospital, Oxford, United Kingdom
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18
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Qiu D, Chen J, Liu J, Luo Z, Jiang W, Huang J, Qiu Z, Yue W, Wu L. Expression of microRNA let-7a positively correlates with hepatitis B virus replication in hepatocellular carcinoma tissues. Exp Biol Med (Maywood) 2017; 242:939-944. [PMID: 28440732 DOI: 10.1177/1535370217697382] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Let-7a miRNA is downregulated in various cancers. However, in hepatocellular carcinoma (HCC) patients infected with hepatitis B virus (HBV), the relationship between let-7a and HBV replication has not been fully elucidated. Liver specimens were collected from 23 HCC patients with chronically active HBV. The serum levels of the HBV antigens hepatitis B surface antigen (HBsAg) and hepatitis B virus e antigen (HBeAg), and the HBV antibodies, anti-HBs, anti-HBe and anti-hepatitis B core antigen (anti-HBc) were measured using the microparticle enzyme immunoassay. Let-7a levels and HBV DNA copy numbers were measured by quantitative real-time PCR (qRT-PCR) and analyzed statistically. A let-7a specific antisense oligonucleotide was introduced to the HBV-producing cell line HepG2.2.15 and a change in HBV DNA copy numbers was assessed by qRT-PCR. HCC patients with highly active HBV replication (>106 DNA copies/mL) showed higher levels of serum HBsAg and anti-HBc than patients with less active HBV replication (<103 DNA copies/mL). The level of let-7a was lower in malignant tissues than in adjacent normal tissues. However, patients with highly active HBV replication demonstrated a significantly higher level of let-7a in hepatocarcinoma tissue than patients with less active HBV replication ( P < 0.05). A higher level of let-7a was observed in the HBV-producing cell line HepG2.2.15 than in HepG2 cells ( P < 0.05), and let-7a down-regulation by antisense oligonucleotides led to a reduction in HBV DNA copy numbers ( P < 0.05), indicating a correlation between the let-7a level and HBV replication. Down-regulation of let-7a reduces HBV replication and could prevent the development of HCC, suggesting it could be an effective therapeutic treatment for HBV infection. Impact statement Although interferon and nucleic acid analogues effectively suppress HBV replication in HBV patients, there is no treatment which eradicates the virus. Moreover, the therapeutic effect can be reduced by virus mutations or drug resistance. Let-7a is a miRNA initially found in the nematode as a master regulator of developmental processes, but also exists in humans. It has been reported that the transcription of let-7a was much lower in HCC than in normal liver tissues and specific miRNA could directly promote virus replication. Therefore we hypothesized that transcription of let-7a promotes HBV replication, which might compromise the therapeutic effects of antivirus treatments. In our present study, we demonstrated a correlation between let-7a transcription and HBV replication in surgical specimens obtained from patients with HCC, as well as in HCC cell lines. Our finding might be the base for a new approach to improve HBV infection treatments in the future.
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Affiliation(s)
- Dongni Qiu
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Jian Chen
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Jie Liu
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Zhongguang Luo
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Weiru Jiang
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Jianping Huang
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Zhibing Qiu
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Wenjie Yue
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
| | - Lijun Wu
- Department of Gastroenterology, Huashan Hospital Affiliated to Fudan University, No. 12 Wulumuqi Zhong Road, Shanghai 200040, China
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