|
1
|
Li Q, Wu K, Zhang Y, Liu Y, Wang Y, Chen Y, Sun S, Duan C. Construction of HBV-HCC prognostic model and immune characteristics based on potential genes mining through protein interaction networks. J Cancer Res Clin Oncol 2023; 149:11263-11278. [PMID: 37358667 DOI: 10.1007/s00432-023-04989-4] [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: 04/25/2023] [Accepted: 06/15/2023] [Indexed: 06/27/2023]
Abstract
OBJECTIVE To search for human protein-coding genes related to hepatocellular carcinoma (HCC) in the context of hepatitis B virus (HBV) infection, and perform prognosis risk assessment. METHODS Genes related to HBV-HCC were selected through literature screening and protein-protein interaction (PPI) network database analysis. Prognosis potential genes (PPGs) were identified using Cox regression analysis. Patients were divided into high-risk and low-risk groups based on PPGs, and risk scores were calculated. Kaplan-Meier plots were used to analyze overall survival rates, and the results were predicted based on clinicopathological variables. Association analysis was also conducted with immune infiltration, immune therapy, and drug sensitivity. Experimental verification of the expression of PPGs was done in patient liver cancer tissue and normal liver tissue adjacent to tumors. RESULTS The use of a prognosis potential genes risk assessment model can reliably predict the prognosis risk of patients, demonstrating strong predictive ability. Kaplan-Meier analysis showed that the overall survival rate of the low-risk group was significantly higher than that of the high-risk group. There were significant differences between the two subgroups in terms of immune infiltration and IC50 association analysis. Experimental verification revealed that CYP2C19, FLNC, and HNRNPC were highly expressed in liver cancer tissue, while UBE3A was expressed at a lower level. CONCLUSION PPGs can be used to predict the prognosis risk of HBV-HCC patients and play an important role in the diagnosis and treatment of liver cancer. They also reveal their potential role in the tumor immune microenvironment, clinical-pathological characteristics, and prognosis.
Collapse
Affiliation(s)
- Qingxiu Li
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Kejia Wu
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Yiqi Zhang
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Yuxin Liu
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Yalan Wang
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China
| | - Yong Chen
- Department of Hepatobillary Surgery, The First Affiliated Hospital, Chongqing Medical University, Chongqing, 400016, China
| | - Shuangling Sun
- Chongqing Medical and Pharmaceutical College, No. 82, University Town Middle Road, Shapingba District, Chongqing, 400016, China
| | - Changzhu Duan
- Department of Cell Biology and Medical Genetics, Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
| |
Collapse
|
|
2
|
Wang MD, Xiang H, Hong TY, Mierxiati A, Yan FH, Zhang L, Wang C. Integrated analysis of intratumoral biomarker and tumor-associated macrophage to improve the prognosis prediction in cancer patients. BMC Cancer 2023; 23:593. [PMID: 37370037 DOI: 10.1186/s12885-023-11027-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Accepted: 05/30/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND The lack of effective and accurate predictive indicators remains a major bottleneck for the improvement of the prognosis of patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Hepatitis B virus X (HBx) has been widely suggested as a critical pathogenic protein for HBV-driven liver carcinogenesis, while tumor-associated macrophage (TAM) infiltration is also closely related to the tumorigenesis and progression of HCC. However, few studies have determined whether combining HBx expression with TAM populations could increase the accuracy of prognostic prediction for HBV-related HCC. METHODS The study cohort enrolling 251 patients with HBV-related HCC was randomly split into a training and a validation group (ratio 1:1). The expression levels of HBx and TAM marker CD68 in HCC samples were detected by immunohistochemistry. Kaplan-Meier curves, Cox regression and Harrell's concordance index (C-index) analysis were conducted to evaluate the prognostic significance of these indicators alone or in combination. RESULTS The expression level of HBx was strongly correlated with CD68+ TAM infiltration in HCC tissues. Elevated HBx or CD68 expression indicated poorer overall survival (OS) and progression-free survival (PFS) after hepatectomy, and both of them were independent risk factors for postoperative survival. Meanwhile, patients with both high HBx and CD68 levels had worst clinical outcomes. Moreover, integrating HBx and CD68 expression with clinical indicators (tumor size and micro-vascular invasion) showed the best prognostic potential with highest C-index value for survival predictivity, and this proposed model also performed better than several conventional classifications of HCC. CONCLUSION Combining the expression of intratumoral HBx, CD68+ TAM population and clinical variables could enable better prognostication for HBV-related HCC after hepatectomy, thus providing novel insights into developing more effective clinical prediction model based on both molecular phenotypes and tumor-immune microenvironment.
Collapse
Affiliation(s)
- Ming-Da Wang
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Navy Medical University, Shanghai, 200433, China
| | - Hao Xiang
- The Third Affiliated Hospital of Zunyi Medical University, The First People's Hospital of Zunyi), Guizhou, 563000, China
| | - Tian-Yu Hong
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
| | - Abudurexiti Mierxiati
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China
| | - Fei-Hu Yan
- Department of Colorectal Surgery, Shanghai Changhai Hospital, Navy Medical University, Shanghai, 200433, China.
| | - Ling Zhang
- Department of Obstetrics and Gynecology, School of Medicine, Chengdu Women's and Children's Central Hospital, University of Electronic Science and Technology of China, Sichuan, 610000, China.
| | - Chao Wang
- Shanghai Health Commission Key Lab of Artificial Intelligence-Based Management of Inflammation and Chronic Diseases, Gongli Hospital, Navy Medical University, 219 Miaopu Road, Shanghai, 200135, China.
- Department of Urinary Surgery, Gongli Hospital, Navy Medical University, Shanghai, 200135, China.
| |
Collapse
|
|
3
|
Padarath K, Deroubaix A, Kramvis A. The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma. Viruses 2023; 15:v15040857. [PMID: 37112837 PMCID: PMC10144019 DOI: 10.3390/v15040857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.
Collapse
|
|
4
|
Shen C, Jiang X, Li M, Luo Y. Hepatitis Virus and Hepatocellular Carcinoma: Recent Advances. Cancers (Basel) 2023; 15:533. [PMID: 36672482 PMCID: PMC9856776 DOI: 10.3390/cancers15020533] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 01/08/2023] [Accepted: 01/13/2023] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) remains a global health challenge, causing 600,000 deaths each year. Infectious factors, including hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatitis D virus (HDV), have long been considered the major risk factors for the development and progression of HCC. These pathogens induce hepatocyte transformation through a variety of mechanisms, including insertional mutations caused by viral gene integration, epigenetic changes, and the induction of long-term immune dysfunction. The discovery of these mechanisms, while advancing our understanding of the disease, also provides targets for new diagnostic and therapeutic approaches. In addition, the discovery and research of chronic HEV infection over the past decade indicate that this common hepatitis virus also seems to have the potential to induce HCC. In this review, we provide an overview of recent studies on the link between hepatitis virus and HCC, as well as new diagnostic and therapeutic approaches to HCC based on these findings. Finally, we also discuss the potential relationship between HEV and HCC. In conclusion, these associations will further optimize the diagnosis and treatment of infection-associated HCC and call for better management policies.
Collapse
Affiliation(s)
| | | | - Mei Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yao Luo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
5
|
Comparative RNA-Sequencing Analysis Reveals High Complexity and Heterogeneity of Transcriptomic and Immune Profiles in Hepatocellular Carcinoma Tumors of Viral (HBV, HCV) and Non-Viral Etiology. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58121803. [PMID: 36557005 PMCID: PMC9785216 DOI: 10.3390/medicina58121803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022]
Abstract
Background and Objectives: Hepatocellular carcinoma (HCC), the most common type of primary liver cancer, is the leading cause of cancer-related mortality. It arises and progresses against fibrotic or cirrhotic backgrounds mainly due to infection with hepatitis viruses B (HBV) or C (HCV) or non-viral causes that lead to chronic inflammation and genomic changes. A better understanding of molecular and immune mechanisms in HCC subtypes is needed. Materials and Methods: To identify transcriptional changes in primary HCC tumors with or without hepatitis viral etiology, we analyzed the transcriptomes of 24 patients by next-generation sequencing. Results: We identified common and unique differentially expressed genes for each etiological tumor group and analyzed the expression of SLC, ATP binding cassette, cytochrome 450, cancer testis, and heat shock protein genes. Metascape functional enrichment analysis showed mainly upregulated cell-cycle pathways in HBV and HCV and upregulated cell response to stress in non-viral infection. GeneWalk analysis identified regulator, hub, and moonlighting genes and highlighted CCNB1, ACTN2, BRCA1, IGF1, CDK1, AURKA, AURKB, and TOP2A in the HCV group and HSF1, HSPA1A, HSP90AA1, HSPB1, HSPA5, PTK2, and AURKB in the group without viral infection as hub genes. Immune infiltrate analysis showed that T cell, cytotoxic, and natural killer cell markers were significantly more highly expressed in HCV than in non-viral tumors. Genes associated with monocyte activation had the highest expression levels in HBV, while high expression of genes involved in primary adaptive immune response and complement receptor activity characterized tumors without viral infection. Conclusions: Our comprehensive study underlines the high degree of complexity of immune profiles in the analyzed groups, which adds to the heterogeneous HCC genomic landscape. The biomarkers identified in each HCC group might serve as therapeutic targets.
Collapse
|
|
6
|
Xia H, Huang Z, Wang Z, Liu S, Zhao X, You J, Xu Y, Yam JWP, Cui Y. Glucometabolic reprogramming: From trigger to therapeutic target in hepatocellular carcinoma. Front Oncol 2022; 12:953668. [PMID: 35912218 PMCID: PMC9336635 DOI: 10.3389/fonc.2022.953668] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/27/2022] [Indexed: 12/11/2022] Open
Abstract
Glucose, the central macronutrient, releases energy as ATP through carbon bond oxidation and supports various physiological functions of living organisms. Hepatocarcinogenesis relies on the bioenergetic advantage conferred by glucometabolic reprogramming. The exploitation of reformed metabolism induces a uniquely inert environment conducive to survival and renders the hepatocellular carcinoma (HCC) cells the extraordinary ability to thrive even in the nutrient-poor tumor microenvironment. The rewired metabolism also confers a defensive barrier which protects the HCC cells from environmental stress and immune surveillance. Additionally, targeted interventions against key players of HCC metabolic and signaling pathways provide promising prospects for tumor therapy. The active search for novel drugs based on innovative mutation targets is warranted in the future for effectively treating advanced HCC and the preoperative downstage. This article aims to review the regulatory mechanisms and therapeutic value of glucometabolic reprogramming on the disease progression of HCC, to gain insights into basic and clinical research.
Collapse
Affiliation(s)
- Haoming Xia
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Ziyue Huang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhensheng Wang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Shuqiang Liu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xudong Zhao
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Junqi You
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yi Xu
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, China
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Yi Xu, ; Judy Wai Ping Yam, ; Yunfu Cui,
| | - Judy Wai Ping Yam
- Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Yi Xu, ; Judy Wai Ping Yam, ; Yunfu Cui,
| | - Yunfu Cui
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Yi Xu, ; Judy Wai Ping Yam, ; Yunfu Cui,
| |
Collapse
|
|
7
|
Guan Y, Sun B, Zhang S, Zhuang Y, Huang Y, Lin M, Zheng R, Chen D, Shi Y, Wang Y. Hepatitis B Virus Induces Microtubule Stabilization to Promote Productive Infection through Upregulating Microtubule-associated Protein 1S. J Clin Transl Hepatol 2022; 10:467-473. [PMID: 35836766 PMCID: PMC9240238 DOI: 10.14218/jcth.2021.00090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 06/05/2021] [Accepted: 06/09/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND AIMS Continuous release and transmission of hepatitis B virus (HBV) is one of the main factors leading to chronic hepatitis B (CHB) infection. However, the mechanism of HBV-host interaction for optimal viral transport is unclear. Hence, we aimed to explore how HBV manipulates microtubule-associated protein 1S (MAP1S) and microtubule (MT) to facilitate its transport and release. METHODS The expression of MAP1S or acetylated MT was investigated by immunofluorescence, RT-PCR, immunoblotting, and plasmid transfection. MAP1S overexpression or knockdown was performed by lentiviral infection or sh-RNA transfection, respectively. HBV DNA was quantified using q-PCR. RESULTS Significantly higher level of MAP1S in HepG2215 cells compared with HepG2 cells was detected using RT-PCR (p<0.01) and immunoblotting (p<0.001). Notably, stronger MAP1S expression was observed in the liver tissues of patients with CHB than in healthy controls. MAP1S overexpression or knockdown demonstrated that MAP1S promoted MT acetylation and reduced the ratio of HBV DNA copies inside to outside cells. Further, transfection with the hepatitis B virus X protein (HBx)-expressing plasmids induced significantly higher level of MAP1S than that in controls (p<0.0001), whereas HBVX- mutant-encoding HBV proteins (surface antigen, core protein, and viral DNA polymerase) hardly affected its expression. CONCLUSIONS These results demonstrate that HBx induces the formation of stable MTs to promote the release of HBV particles through upregulating MAP1S. Thus, our studies delineate a unique molecular pathway through which HBV manipulates the cytoskeleton to facilitate its own transportation, and indicate the possibility of targeting MAP1S pathway for treatment of patients with CHB.
Collapse
Affiliation(s)
- Yuanyue Guan
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Bin Sun
- Department of Intervention Therapy Center of Tumor and Liver Diseases, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Shijie Zhang
- Department of Pathology, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yuan Zhuang
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Yanxiang Huang
- Clinical Laboratory Center, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Minghua Lin
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Rongling Zheng
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Dexi Chen
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
| | - Ying Shi
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
- Correspondence to: Yanjun Wang and Ying Shi, Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing 100069, China. ORCID: https://orcid.org/0000-0002-9602-6816 (YW), https://orcid.org/0000-0001-5838-0817 (YS). Tel: +86-10-8399-7407, E-mail: (YW), (YS)
| | - Yanjun Wang
- Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Beijing, China
- Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing, China
- Correspondence to: Yanjun Wang and Ying Shi, Department of Beijing Institute of Hepatology, Beijing You An Hospital, Capital Medical University, Department of Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer, Beijing You An Hospital, Capital Medical University, Beijing 100069, China. ORCID: https://orcid.org/0000-0002-9602-6816 (YW), https://orcid.org/0000-0001-5838-0817 (YS). Tel: +86-10-8399-7407, E-mail: (YW), (YS)
| |
Collapse
|
|
8
|
Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
Collapse
Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| |
Collapse
|
|
9
|
Liu Z, Zhou X, Zheng P, Bu C, Yan X, Yu H, Xu Y. Clinical significance of mitogen-activated protein kinase kinase kinases in hepatitis B virus -related hepatocellular carcinoma and underlying mechanism exploration. Bioengineered 2022; 13:6819-6838. [PMID: 35311629 PMCID: PMC9278978 DOI: 10.1080/21655979.2022.2037224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The purpose of this research was to explore the diagnostic/prognostic significance and prospective molecular mechanisms of mitogen-activated protein kinase kinase kinases (MAP3Ks) in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Diagnostic/prognostic significance of MAP3Ks was screened in the GSE1450 data set and validated in the Guangxi cohort. Various bioinformatics tools were used to explore the biological functions of prognosis-related genes. Subsequently, molecular biology assays were used to verify the biological functions and molecular mechanisms of specific gene. MAP3K9 was observed to be differentially expressed in HCC and adjacent tissues with satisfactory diagnostic value. It was discovered in survival analysis that MAP3K13 and MAP3K15 were associated with overall survival (OS) of patients with HBV-related HCC in the GSE1450 data set and the Guangxi cohort. Nomograms were established based on prognosis-related genes and clinical factors for individualized risk assessment. The assays on HCC cells demonstrated that MAP3K13 regulated the death and proliferation of HCC cells by activating the JNK pathway and inducing the expression of apoptosis-related factors. In conclusion, our results suggested that MAP3K9 might serve as a diagnostic biomarker in HBV-related HCC and MAP3K13 and MAP3K15 might serve as useful prognostic biomarkers. Besides, cytological assays prompted that MAP3K13 might impact the prognosis of HCC by regulating the JNK pathway and inducing apoptosis.
Collapse
Affiliation(s)
- Zhengqian Liu
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, P. R. China
| | - Peng Zheng
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| | - Chenheng Bu
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| | - Xiao'ou Yan
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| | - Haizhou Yu
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| | - Yong Xu
- Department of Burn and Plastic Surgery, Yancheng No. 1 People's Hospital, Yancheng, P. R. China
| |
Collapse
|
|
10
|
Kato Y, Tabata H, Sato K, Nakamura M, Saito I, Nakanishi T. Adenovirus Vectors Expressing Eight Multiplex Guide RNAs of CRISPR/Cas9 Efficiently Disrupted Diverse Hepatitis B Virus Gene Derived from Heterogeneous Patient. Int J Mol Sci 2021; 22:10570. [PMID: 34638909 PMCID: PMC8508944 DOI: 10.3390/ijms221910570] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/22/2021] [Accepted: 09/24/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis B virus (HBV) chronically infects more than 240 million people worldwide, causing chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). Genome editing using CRISPR/Cas9 could provide new therapies because it can directly disrupt HBV genomes. However, because HBV genome sequences are highly diverse, the identical target sequence of guide RNA (gRNA), 20 nucleotides in length, is not necessarily present intact in the target HBV DNA in heterogeneous patients. Consequently, possible genome-editing drugs would be effective only for limited numbers of patients. Here, we show that an adenovirus vector (AdV) bearing eight multiplex gRNA expression units could be constructed in one step and amplified to a level sufficient for in vivo study with lack of deletion. Using this AdV, HBV X gene integrated in HepG2 cell chromosome derived from a heterogeneous patient was cleaved at multiple sites and disrupted. Indeed, four targets out of eight could not be cleaved due to sequence mismatches, but the remaining four targets were cleaved, producing irreversible deletions. Accordingly, the diverse X gene was disrupted at more than 90% efficiency. AdV containing eight multiplex gRNA units not only offers multiple knockouts of genes, but could also solve the problems of heterogeneous targets and escape mutants in genome-editing therapy.
Collapse
MESH Headings
- Adenoviridae/genetics
- Adenoviridae/physiology
- CRISPR-Cas Systems
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/therapy
- Carcinoma, Hepatocellular/virology
- Cell Line, Tumor
- Gene Editing/methods
- Genetic Vectors/genetics
- HEK293 Cells
- Hep G2 Cells
- Hepatitis B virus/genetics
- Hepatitis B virus/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/therapy
- Hepatitis B, Chronic/virology
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/therapy
- Liver Neoplasms/virology
- RNA, Guide, CRISPR-Cas Systems/genetics
- RNA, Guide, CRISPR-Cas Systems/metabolism
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Viral Regulatory and Accessory Proteins/genetics
- Viral Regulatory and Accessory Proteins/metabolism
- Virus Replication/genetics
Collapse
Affiliation(s)
- Yuya Kato
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
| | - Hirotaka Tabata
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
| | - Kumiko Sato
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
| | - Mariko Nakamura
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Center for Biomedical Research Resources, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Izumu Saito
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Department of Physiology, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Tomoko Nakanishi
- Laboratory of Virology, Institute of Microbial Chemistry (BIKAKEN), Microbial Chemistry Foundation, Shinagawa-ku, Tokyo 141-0021, Japan; (Y.K.); (H.T.); (M.N.); (T.N.)
- Laboratory of Molecular Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan;
- Center for Biomedical Research Resources, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| |
Collapse
|
|
11
|
Merle P. Pragmatic tools for the prediction and potential early diagnosis of hepatitis B virus-related hepatocellular carcinoma? Clin Res Hepatol Gastroenterol 2021; 45:101722. [PMID: 34146725 DOI: 10.1016/j.clinre.2021.101722] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 04/24/2021] [Indexed: 02/04/2023]
Affiliation(s)
- Philippe Merle
- Unité d'Hépatologie et Gastroentérologie, Hôpital de la Croix Rousse, Hospices Civils de Lyon, France; Centre de Recherche en Cancérologie de Lyon, INSERM U1052, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France.
| |
Collapse
|
|
12
|
Alfano V, Zeisel MB, Levrero M, Guerrieri F. The lncRNAs in HBV-Related HCCs: Targeting Chromatin Dynamics and Beyond. Cancers (Basel) 2021; 13:3115. [PMID: 34206504 PMCID: PMC8268133 DOI: 10.3390/cancers13133115] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 06/18/2021] [Accepted: 06/19/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents the fourth leading and fastest rising cause of cancer death (841,000 new cases and 782,000 deaths annually), and hepatitis B (HBV), with 250 million people chronically infected at risk of developing HCC, accounts for >50% of the cases worldwide. Long non-coding RNAs (lncRNAs), untranslated transcripts longer than 200 nucleotides, are implicated in gene regulation at the transcriptional and post-transcriptional levels, exerting their activities both in the nuclear and cytoplasmic compartments. Thanks to high-throughput sequencing techniques, several lncRNAs have been shown to favor the establishment of chronic HBV infection, to change the host transcriptome to establish a pro-carcinogenic environment, and to directly participate in HCC development and progression. In this review, we summarize current knowledge on the role of lncRNAs in HBV infection and HBV-related liver carcinogenesis and discuss the potential of lncRNAs as predictive or diagnostic biomarkers.
Collapse
Affiliation(s)
- Vincenzo Alfano
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France; (V.A.); (M.B.Z.)
| | - Mirjam B. Zeisel
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France; (V.A.); (M.B.Z.)
| | - Massimo Levrero
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France; (V.A.); (M.B.Z.)
- Hospices Civils de Lyon, Hôpital Croix Rousse, Service d’Hépato-Gastroentérologie, 69004 Lyon, France
- Department of Medicine SCIAC, University of Rome La Sapienza, 00161 Rome, Italy
| | - Francesca Guerrieri
- Cancer Research Center of Lyon (CRCL), UMR Inserm 1052 CNRS 5286 Mixte CLB, Université de Lyon 1 (UCBL1), 69003 Lyon, France; (V.A.); (M.B.Z.)
| |
Collapse
|
|
13
|
Egan KM, Kim Y, Bender N, Hodge JM, Coghill AE, Smith-Warner SA, Rollison DE, Teras LR, Grimsrud TK, Waterboer T. Prospective investigation of polyomavirus infection and the risk of adult glioma. Sci Rep 2021; 11:9642. [PMID: 33953301 PMCID: PMC8100283 DOI: 10.1038/s41598-021-89133-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 04/16/2021] [Indexed: 12/23/2022] Open
Abstract
Glioma is an aggressive primary tumor of the brain with a poorly understood etiology. We studied the association of 4 human polyomaviruses (HPyV)—JC virus (JCV), BK virus (BKV), human polyomavirus 6 (HPyV6), and Merkel cell polyomavirus (MCPyV) with glioma risk within the Cancer Prevention Study II in the US (CPS-II) and the Janus Serum Bank in Norway. Cohort participants subsequently diagnosed with glioma from the CPS-II (n = 37) and Janus Serum Bank (n = 323), a median of 6.9 and 15.4 years after blood collection, respectively, were matched to individual controls on age, sex, and date of blood draw. Serum antibodies to the major viral capsid protein (VP1) were used to establish infection history for each polyomavirus. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In the Janus Serum Bank, MCPyV infection was associated with a higher risk of glioma overall (OR: 1.56; 95% CI 1.10, 2.19). A modest, nonsignificant positive association with MCPyV infection was also observed in CPS-II (OR: 1.29; 95% CI 0.54, 3.08). In both cohorts, glioma risk was not significantly related to infection with JCV, BKV or HPyV6. The present study suggests that MCPyV infection may increase glioma risk.
Collapse
Affiliation(s)
- Kathleen M Egan
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
| | - Youngchul Kim
- Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Noemi Bender
- Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120, Heidelberg, Germany
| | - James M Hodge
- Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA
| | - Anna E Coghill
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Stephanie A Smith-Warner
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA
| | - Dana E Rollison
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA
| | - Lauren R Teras
- Department of Population Science, American Cancer Society, Atlanta, GA, 30303, USA
| | - Tom K Grimsrud
- Department of Research, Cancer Registry of Norway, 0379, Oslo, Norway
| | - Tim Waterboer
- Infections and Cancer Epidemiology, German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ), 69120, Heidelberg, Germany
| |
Collapse
|
|
14
|
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
|
|
15
|
Bezzecchi E, Ronzio M, Mantovani R, Dolfini D. NF-Y Overexpression in Liver Hepatocellular Carcinoma (HCC). Int J Mol Sci 2020; 21:E9157. [PMID: 33271832 PMCID: PMC7731131 DOI: 10.3390/ijms21239157] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/24/2020] [Accepted: 11/24/2020] [Indexed: 12/24/2022] Open
Abstract
NF-Y is a pioneer trimeric transcription factor formed by the Histone Fold Domain (HFD) NF-YB/NF-YC subunits and NF-YA. Three subunits are required for DNA binding. CCAAT-specificity resides in NF-YA and transactivation resides in Q-rich domains of NF-YA and NF-YC. They are involved in alternative splicing (AS). We recently showed that NF-YA is overexpressed in breast and lung carcinomas. We report here on the overexpression of all subunits in the liver hepatocellular carcinoma (HCC) TCGA database, specifically the short NF-YAs and NF-YC2 (37 kDa) isoforms. This is observed at all tumor stages, in viral-infected samples and independently from the inflammatory status. Up-regulation of NF-YAs and NF-YC, but not NF-YB, is associated to tumors with mutant p53. We used a deep-learning-based method (DeepCC) to extend the partitioning of the three molecular clusters to all HCC TCGA tumors. In iCluster3, CCAAT is a primary matrix found in promoters of up-regulated genes, and cell-cycle pathways are enriched. Finally, clinical data indicate that, globally, only NF-YAs, but not HFD subunits, correlate with the worst prognosis; in iCluster1 patients, however, all subunits correlate. The data show a difference with other epithelial cancers, in that global overexpression of the three subunits is reported and clinically relevant in a subset of patients; yet, they further reinstate the regulatory role of the sequence-specific subunit.
Collapse
Affiliation(s)
| | | | | | - Diletta Dolfini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Via Celoria 26, 20133 Milano, Italy; (E.B.); (M.R.); (R.M.)
| |
Collapse
|
|
16
|
Yang M, Yang G, Li F, Ou M, Li C, Chen J, Lin H, Zhang Y, Xue W, Wu Y, Xu Y, Sui W, Dai Y. HBV integrated genomic characterization revealed hepatocyte genomic alterations in HBV-related hepatocellular carcinomas. Mol Clin Oncol 2020; 13:79. [PMID: 33062269 PMCID: PMC7549396 DOI: 10.3892/mco.2020.2149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 08/28/2020] [Indexed: 12/04/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignancies that is closely associated with the Hepatitis B virus (HBV). HBV integration into host genomes can induce instability and the aberrant expression of human genomic DNA. To directly assess HBV integration breakpoints at whole genome level, four small sequencing libraries were constructed and the HBV integration profiles of four patients with HCC were characterized. In total, the current study identified 11,800,974, 11,216,998, 11,026,546 and 11,607,842 clean reads for patients 1-3 and 4, respectively, of which 92.82, 95.95, 97.21 and 97.29% were properly aligned to the hybrid reference genome. In addition, 220 HBV integration events were detected from the tumor tissues of four patients with HCC and an average of 55 breakpoints per sample was calculated. The results indicated that HBV integration events may be implicated in HCC physiologies and diseases. The results acquired may also provide insight into the pathogenesis of HCC, which may be valuable for future HCC therapy.
Collapse
Affiliation(s)
- Ming Yang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Guiqi Yang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Fengyan Li
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Minglin Ou
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Chunhong Li
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,College of Life Science, Guangxi Normal University, Guilin, Guangxi 541004, P.R. China
| | - Jiejing Chen
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Hua Lin
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yue Zhang
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Wen Xue
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yan Wu
- Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Yong Xu
- Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| | - Weiguo Sui
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China
| | - Yong Dai
- Guangxi Key Laboratory of Metabolic Disease Research, Central Laboratory, Nephrology Department of Guilin No. 924 Hospital, Guilin, Guangxi 541002, P.R. China.,Clinical Medical Research Center of The Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China
| |
Collapse
|
|
17
|
Antiviral therapy and hepatocellular carcinoma risk in hepatitis B patients with cirrhosis. Eur J Gastroenterol Hepatol 2020; 32:1207-1211. [PMID: 32129773 DOI: 10.1097/meg.0000000000001639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Our goal was to evaluate the effect of antiviral therapy on hepatocellular carcinoma incidence for cirrhotic patients with lower hepatitis B virus DNA levels. METHODS Consecutive cirrhosis patients from a US cohort (n = 381) and 408 patients from a Taiwan cohort were enrolled. Patients were classified into a low (<20 IU/ml) and high hepatitis B virus DNA group (≥20 IU/ml), and each was further stratified into treated and untreated subgroups. RESULTS Except for hepatitis B e antigen, baseline characteristics were similar for both hepatitis B virus DNA groups. Antiviral therapy significantly reduced hepatocellular carcinoma incidence in cirrhotic patients with hepatitis B virus DNA ≥20 IU/ml at 5-years (12.2% vs. 22.8%) and 10-years (23.3% vs. 37.2%) (P = 0.0018). For cirrhotic patients with hepatitis B virus DNA <20 IU/ml, there was no statistically significant difference in cumulative hepatocellular carcinoma incidence between the treated and untreated groups. After adjusting for age, sex, and hepatitis B e antigen status, antiviral therapy was an independent predictor (hazard ratio 0.43, P < 0.0001) for reduced hepatocellular carcinoma risk in patients with hepatitis B virus DNA ≥20 IU/ml. CONCLUSION Antiviral therapy was associated with a 57% reduction in hepatocellular carcinoma incidence in chronic hepatitis B patients with cirrhosis and hepatitis B virus DNA as low as 20 IU/ml (but no lower). However, hepatocellular carcinoma incidence remained substantial, regardless of hepatitis B virus DNA levels and treatment status, highlighting the need for ongoing hepatocellular carcinoma surveillance for all cirrhotic hepatitis B virus patients.
Collapse
|
|
18
|
Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals. Biomedicines 2020. [PMID: 32630610 DOI: 10.3390/biomedicines8060175.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone.
Collapse
|
|
19
|
Kishta S, Tabll A, Omanovic Kolaric T, Smolic R, Smolic M. Risk Factors Contributing to the Occurrence and Recurrence of Hepatocellular Carcinoma in Hepatitis C Virus Patients Treated with Direct-Acting Antivirals. Biomedicines 2020; 8:175. [PMID: 32630610 PMCID: PMC7344618 DOI: 10.3390/biomedicines8060175] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/09/2020] [Accepted: 06/16/2020] [Indexed: 02/07/2023] Open
Abstract
Although hepatitis C virus (HCV) RNA may be eliminated from blood circulation by direct-acting antivirals (DAA) therapy as assessed by real-time polymerase chain reaction (PCR), HCV RNA can still be present in liver tissue, and this is known as occult HCV. There has been a lot of controversy surrounding the recurrence of hepatocellular carcinoma (HCC) after DAA treatment of hepatic cells infected with chronic HCV. One of the main risk factors that leads to de novo HCC is the chronicity of HCV in hepatic cells. There are many studies regarding the progression of HCV-infected hepatic cells to HCC. However, there is a lack of research on the different molecular mechanisms that lead to the progression of chronic HCV infection to HCC, as well as on the effect of HCV on the alteration of DNA ploidy, which eventually leads to a recurrence of HCC after DAA treatment. In this review article, we will address some risk factors that could lead to the development/recurrence of HCC after treatment of HCV with DAA therapy, such as the role of liver cirrhosis, the alteration of DNA ploidy, the reactivation of hepatitis B virus (HBV), the role of cytokines and the alteration of the immune system, concomitant non- alcoholic fatty liver disease (NAFLD), obesity, alcohol consumption and also occult HCV infection/co-infection. Clinicians should be cautious considering that full eradication of hepatocarcinogenesis cannot be successfully accomplished by anti-HCV treatment alone.
Collapse
Affiliation(s)
- Sara Kishta
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, El Behooth Street, Dokki 12622, Egypt; (S.K.); (A.T.)
- Virology Division, Federal Institute for Vaccines and Biomedicines, Paul-Ehrlich-Institute, Paul-Ehrlich-Straße 51-59, 63225 Langen, Germany
| | - Ashraf Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division, National Research Centre, El Behooth Street, Dokki 12622, Egypt; (S.K.); (A.T.)
- Department of immunology, Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 11517, Egypt
| | - Tea Omanovic Kolaric
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (T.O.K.); (R.S.)
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Crkvena 21, HR-3100 Osijek, Croatia
| | - Robert Smolic
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (T.O.K.); (R.S.)
- Division of Gastroenterology/Hepatology, Department of Medicine, University Hospital Osijek, J. Huttlera 4, HR-3100 Osijek, Croatia
| | - Martina Smolic
- Faculty of Medicine Osijek, Josip Juraj Strossmayer University of Osijek, J. Huttlera 4, HR-31000 Osijek, Croatia; (T.O.K.); (R.S.)
- Faculty of Dental Medicine and Health Osijek, Josip Juraj Strossmayer University of Osijek, Crkvena 21, HR-3100 Osijek, Croatia
| |
Collapse
|
|
20
|
Jia L, Gao Y, He Y, Hooper JD, Yang P. HBV induced hepatocellular carcinoma and related potential immunotherapy. Pharmacol Res 2020; 159:104992. [PMID: 32505833 DOI: 10.1016/j.phrs.2020.104992] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/16/2020] [Accepted: 05/31/2020] [Indexed: 02/06/2023]
Abstract
Chronic infection of Hepatitis B virus (HBV) has long been recognized as a major risk factor in the initiation and development of hepatocellular carcinoma (HCC), contributing to over half the cases of HCC worldwide. Transformation of the liver with HBV infection to HCC mainly results from long-term interaction between HBV and the host hepatocytes via a variety of mechanisms, including HBV DNA integration, prolonged expression of the viral HBx regulatory protein and/or aberrant preS/S envelope proteins, and epigenetic dysregulation of tumor suppressor genes. While there have been several failures in the development of drugs for HCC, the immune-tolerant microenvironment of this malignancy suggests that immunotherapeutic agents could provide benefits for these patients. This is supported by recent data showing that immunotherapy has promising activity in patients with advanced HCC. In this review, we provide an overview of HBV-induced HCC and recent immune based approaches for the treatment of HCC patients.
Collapse
Affiliation(s)
- Liyang Jia
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yanan Gao
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China
| | - Yaowu He
- Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - John D Hooper
- Mater Research Institute - University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
| | - Pengyuan Yang
- Key Laboratory of Infection and Immunity of CAS, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China; University of Chinese Academy of Sciences, 100049 Beijing, China.
| |
Collapse
|
|
21
|
Dandri M. Epigenetic modulation in chronic hepatitis B virus infection. Semin Immunopathol 2020; 42:173-185. [PMID: 32185454 PMCID: PMC7174266 DOI: 10.1007/s00281-020-00780-6] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 01/08/2020] [Indexed: 02/06/2023]
Abstract
The human hepatitis B virus (HBV) is a small-enveloped DNA virus causing acute and chronic hepatitis. Despite the existence of an effective prophylactic vaccine and the strong capacity of approved antiviral drugs to suppress viral replication, chronic HBV infection (CHB) continues to be a major health burden worldwide. Both the inability of the immune system to resolve CHB and the unique replication strategy employed by HBV, which forms a stable viral covalently closed circular DNA (cccDNA) minichromosome in the hepatocyte nucleus, enable infection persistence. Knowledge of the complex network of interactions that HBV engages with its host is still limited but accumulating evidence indicates that epigenetic modifications occurring both on the cccDNA and on the host genome in the course of infection are essential to modulate viral activity and likely contribute to pathogenesis and cancer development. Thus, a deeper understanding of epigenetic regulatory processes may open new venues to control and eventually cure CHB. This review summarizes major findings in HBV epigenetic research, focusing on the epigenetic mechanisms regulating cccDNA activity and the modifications determined in infected host cells and tumor liver tissues.
Collapse
Affiliation(s)
- Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Hamburg, Germany.
| |
Collapse
|
|
22
|
Zhang C, Liu P, Zhang C. Hepatitis B virus X protein upregulates alpha-fetoprotein to promote hepatocellular carcinoma by targeting miR-1236 and miR-329. J Cell Biochem 2020; 121:2489-2499. [PMID: 31680299 DOI: 10.1002/jcb.29471] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/10/2019] [Indexed: 12/29/2022]
Abstract
Hepatitis B virus (HBV) infection is the most common cause of hepatocellular carcinoma (HCC) worldwide, wherein the expression of alpha-fetoprotein (AFP) is reactivated to promote tumorgenesis. Hepatitis B virus X protein (HBx) protein encoded by the HBV virus X gene has been considered to be oncogenic and implicated in hepatocarcinogenesis. However, the relationship between HBx and abnormal AFP expression in HCC is yet to be fully understood. To explore the potential regulation of HBx on AFP re-expression in HCC, 97 HCC samples of different etiologies were analyzed, and extremely higher serum AFP levels were found in patients with HBsAg+ . Analyses of HBV-related HCC specimens showed that the expression of AFP was negatively correlated with the levels of miR-1236 and miR-329. Further analyses indicated that HBx promotes the expression of AFP by orchestrating the levels of miR-1236 and miR-329 both in vitro and in vivo. Specifically, miR-1236 and miR-329 bind to the potential target sequences in AFP mRNA 3'-untranslated region to suppress its expression. HBx transfection resulted in the significant decrement of these microRNAs and increment of AFP expression. Moreover, AFP promotes the proliferation of hepatoma cells and attenuates the proapoptotic effect of chemotherapy agents. These findings revealed a novel regulatory mechanism of HBx on the abnormal AFP expression in HCC, which may provide a therapeutic approach for combating HBV-related HCC by targeting the regulation of AFP expression.
Collapse
Affiliation(s)
- Chao Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, China
| | - Peng Liu
- Department of Scientific Research, Central Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Chuanbao Zhang
- National Center for Clinical Laboratories, Beijing Hospital, National Center of Gerontology, Beijing Engineering Research Center of Laboratory Medicine, Beijing, China
| |
Collapse
|
|
23
|
Utilizing Experimental Mouse Model to Identify Effectors of Hepatocellular Carcinoma Induced by HBx Antigen. Cancers (Basel) 2020; 12:cancers12020409. [PMID: 32050622 PMCID: PMC7072678 DOI: 10.3390/cancers12020409] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 01/31/2020] [Accepted: 02/04/2020] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is among the ten most commonly diagnosed cancers and the fourth leading cause of cancer-related death. Patients with hepatitis B virus (HBV) infection are prone to developing chronic liver diseases (i.e., fibrosis and cirrhosis), and the HBV X antigen plays an important role in the development of HCC. The difficulty in detecting HCC at the early stages is one of the main reasons that the death rate approximates the incidence rate. The regulators controlling the downstream liver protein expression from HBV infection are unclear. Mass spectrometric techniques and customized programs were used to identify differentially expressed proteins which may be involved in the development of liver fibrosis and HCC progression in hepatitis B virus X protein transgenic mice (HBx mice). FSTL1, CTSB, and TGF-β enhanced the signaling pathway proteins during the pathogenesis of HBx. Missing proteins can be essential in cell growth, differentiation, apoptosis, migration, metastasis or angiogenesis. We found that LHX2, BMP-5 and GDF11 had complex interactions with other missing proteins and BMP-5 had both tumor suppressing and tumorigenic roles. BMP-5 may be involved in fibrosis and tumorigenic processes in the liver. These results provide us an understanding of the mechanism of HBx-induced disorders, and may serve as molecular targets for liver treatment.
Collapse
|
|
24
|
Tao S, Pan S, Gu C, Wei L, Kang N, Xie Y, Liu J. Characterization and engineering of broadly reactive monoclonal antibody against hepatitis B virus X protein that blocks its interaction with DDB1. Sci Rep 2019; 9:20323. [PMID: 31889135 PMCID: PMC6937242 DOI: 10.1038/s41598-019-56819-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 12/17/2019] [Indexed: 12/20/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) plays diverse roles in both viral life cycle and HBV-related carcinogenesis. Its interaction with DNA damage-binding protein 1 (DDB1) was shown to be essential for engendering cellular conditions favorable for optimal viral transcription and replication. Previously, we described a mouse monoclonal antibody against HBx (anti-HBx 2A7) recognizing HBx encoded by representative strains from 7 of 8 known HBV genotypes. In this work, we further characterized 2A7 in order to explore its potential usefulness in HBx-targeting applications. We demonstrated that 2A7 recognizes a linear epitope mapped to L89PKVLHKR96 on HBx, a segment that is highly conserved across genotypes and coincidentally overlaps with the DDB1-interacting segment. HBx-DDB1 binding could be inhibited by 2A7 in vitro, suggesting therapeutic potential. Nucleic acid and amino acid sequences of 2A7 were then obtained, which allowed construction of recombinant antibody and single chain variable fragments (scFv). 2A7-derived recombinant antibody and scFv recapitulate 2A7's HBx-binding capacity and epitope specificity. We also reported preliminary results using cell-penetrating peptide for delivering 2A7 antibody across cell membrane to target intracellular HBx. Anti-HBx 2A7 and 2A7-derived scFv characterized here may give rise to novel HBx-targeting diagnostics and therapeutics for HBV- and HBx-related pathologies.
Collapse
Affiliation(s)
- Shuai Tao
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shaokun Pan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Chenjian Gu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lili Wei
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ning Kang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Youhua Xie
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Jing Liu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Department of Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. .,Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
| |
Collapse
|
|
25
|
Wungu CDK, Amin M, Ruslan SEN, Purwono PB, Kholili U, Maimunah U, Setiawan PB, Lusida MI, Soetjipto S, Handajani R. Association between host TNF-α, TGF-β1, p53 polymorphisms, HBV X gene mutation, HBV viral load and the progression of HBV-associated chronic liver disease in Indonesian patients. Biomed Rep 2019; 11:145-153. [PMID: 31565220 PMCID: PMC6759598 DOI: 10.3892/br.2019.1239] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 08/12/2019] [Indexed: 02/07/2023] Open
Abstract
In developing countries, including Indonesia, there is a high mortality rate associated with the progression of hepatitis B virus (HBV)-associated chronic liver disease (CLD). The pathogenesis of HBV infection is influenced by viral and host factors. To determine potential associations between these factors, host single nucleotide polymorphisms (SNPs) on TNF-α, TGF-β1 and p53, HBV X gene mutation and HBV viral load were investigated in patients with HBV-associated CLD in Surabaya, Indonesia. Sera were collected from 87 CLD patients with HBV infection. TNF-α, TGF-β1 and p53 SNPs were genotyped by PCR restriction fragment length polymorphism. The HBV X gene was sequenced and compared with reference strains to determine mutations and the viral load was measured using reverse transcription-quantitative PCR. In Indonesian patients, no association between TNF-α, TGF-β1 and p53 SNPs and CLD or X gene mutation were identified. A total of 23% (20/87) of samples had HBV X gene mutations, including ten substitution types, one deletion and one insertion. Multinomial regression analysis revealed that the K130M/V131I mutations were correlated with CLD progression (OR, 7.629; 95% CI, 1.578-36.884). Significant differences in viral load were found in HBV-infected patients who had X gene mutations, such as R87W/G, I127L/T/N/S and K130M/V131I mutations (P<0.05). The presence of K130M and V131I mutations may be predictive for the progression of HBV-associated CLD in Indonesia.
Collapse
Affiliation(s)
- Citrawati Dyah Kencono Wungu
- Department of Medical Biochemistry, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia.,Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia
| | - Mochamad Amin
- Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia
| | - S Eriaty N Ruslan
- Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia
| | - Priyo Budi Purwono
- Department of Medical Microbiology, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia
| | - Ulfa Kholili
- Department of Internal Medicine, Faculty of Medicine, University of Airlangga, Dr Soetomo General Hospital, Surabaya 60286, Indonesia
| | - Ummi Maimunah
- Department of Internal Medicine, Faculty of Medicine, University of Airlangga, Dr Soetomo General Hospital, Surabaya 60286, Indonesia
| | - Poernomo Boedi Setiawan
- Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia.,Department of Medical Microbiology, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia
| | - Maria Inge Lusida
- Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia.,Department of Medical Microbiology, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia
| | - Soetjipto Soetjipto
- Department of Medical Biochemistry, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia.,Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia
| | - Retno Handajani
- Department of Medical Biochemistry, Faculty of Medicine, University of Airlangga, Surabaya 60131, Indonesia.,Institute of Tropical Disease, University of Airlangga Campus C, Mulyorejo, Surabaya 60286, Indonesia
| |
Collapse
|
|
26
|
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
|
|
27
|
Shinn BJ, Martin A, Coben RM, Conn MI, Prieto J, Kroop H, DiMarino AJ, Hann HW. Persistent risk for new, subsequent new and recurrent hepatocellular carcinoma despite successful anti-hepatitis B virus therapy and tumor ablation: The need for hepatitis B virus cure. World J Hepatol 2019; 11:65-73. [PMID: 30705719 PMCID: PMC6354125 DOI: 10.4254/wjh.v11.i1.65] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 11/14/2018] [Accepted: 12/31/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the most significant hepatocarcinogens. The ultimate goal of anti-HBV treatment is to prevent the development of hepatocellular carcinoma (HCC). During the last two decades, with the use of currently available anti-HBV therapies (lamivudine, entecavir and tenofovir disoproxil fumatate), there has been a decrease in the incidence of HBV-associated HCC (HBV-HCC). Furthermore, several studies have demonstrated a reduction in recurrent or new HCC development after initial HCC tumor ablation. However, during an observation period spanning 10 to 20 years, several case reports have demonstrated the development of new, subsequent new and recurrent HCC even in patients with undetectable serum HBV DNA. The persistent risk for HCC is attributed to the presence of covalently closed circular DNA (cccDNA) in the hepatocyte nucleus which continues to work as a template for HBV replication. While a functional cure (loss of hepatitis B surface antigen and undetectable viral DNA) can be attained with nucleos(t)ide analogues, these therapies do not eliminate cccDNA. Of utmost importance is successful eradication of the transcriptionally active HBV cccDNA from hepatocyte nuclei which would be considered a complete cure. The unpredictable nature of HCC development in patients with chronic HBV infection shows the need for a complete cure. Continued support and encouragement for research efforts aimed at developing curative therapies is imperative. The aims of this minireview are to highlight these observations and emphasize the need for a cure for HBV.
Collapse
Affiliation(s)
- Brianna J Shinn
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Aaron Martin
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Robert M Coben
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Mitchell I Conn
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Jorge Prieto
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Howard Kroop
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Anthony J DiMarino
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
| | - Hie-Won Hann
- Division of Gastroenterology and Hepatology, Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States.
| |
Collapse
|
|
28
|
He B, Peng F, Li W, Jiang Y. Interaction of lncRNA-MALAT1 and miR-124 regulates HBx-induced cancer stem cell properties in HepG2 through PI3K/Akt signaling. J Cell Biochem 2018; 120:2908-2918. [PMID: 30500989 DOI: 10.1002/jcb.26823] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 02/28/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatitis B virus X protein (HBx) plays a crucial role in initiating and promoting HBV-induced hepatocellular carcinoma (HCC) development. Reports indicated that HBx promotes cancer stem cell (CSC) generation, which may be associated with HBV-related HCC. Noncoding RNA miR-124 and long noncoding RNA (lncRNA)-metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were considered to be involved deeply in the progress of HBx-related HCC. Hence, the underlying mechanism of miR-124 and lncRNA-MALAT1 in regulating HBx-promoted CSC needs to be studied. MATERIALS AND METHODS In present study, HepG2-X cell line was induced by transfect HBx into HepG2 cells. Overexpressing of miR-124 or silencing of lncRNA-MALAT1 was completed by transfecting miR-124 mimic or shMALAT1 into HepG2-X cells. HBx-induced CSC properties and tumorigenic potential of HepG2 cells were determined by detecting CSC marker expression, colony formation assay, and xenograft tumorigenesis. The mechanism of HBx-induced CSC properties was explored by PI3K/Akt inhibitor. Interaction of miR-124 and lncRNA-MALAT1 was detected by luciferase reporter assay. RESULTS HBx promoted CSC properties through upregulating stemness markers and reprogramming proteins, and contributed to tumorigenicity of HepG2-X cells both in vivo and in vitro. Inhibition of Akt activation blocked the HBx-stimulated reprogramming proteins and stemness markers. HBx upregulated lncRNA-MALAT1 expression while downregulating miR-124 expression in HepG2-X cells. miR-124 interacts with lncRNA-MALAT1 by direct targeting. Overexpression of miR-124 or silencing of lncRNA-MALAT1 both blocked HBx-induced CSC generation, stemness-related factor activation and tumorigenicity via PI3K/Akt signaling. CONCLUSION Our results demonstrated that miR-124 interact with lncRNA-MALAT1 and involve in regulating HBx-induced CSC properties via PI3K/Akt signaling.
Collapse
Affiliation(s)
- Bo He
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Feng Peng
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Wei Li
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Yongfang Jiang
- Department of Infectious Diseases, Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| |
Collapse
|
|
29
|
Hu Z, Huang P, Yan Y, Zhou Z, Wang J, Wu G. Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion. Biochem Biophys Res Commun 2018; 508:79-86. [PMID: 30471857 DOI: 10.1016/j.bbrc.2018.11.091] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Accepted: 11/14/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus X protein (HBx) is involved in the initiation and progression of hepatocellular carcinoma (HCC) by regulating the host protein-coding genes. In this study, we showed that HBx altered the expression of lncRNAs to promote the progression of HCC. lncRNA microarray and quantitative reverse-transcription polymerase chain reactions (qRT-PCRs) were performed to identify lncRNAs that were differentially regulated by HBx in HCC cells and tissues. Protein, mRNA, and lncRNA expression analyses; cell cycle and apoptosis analyses; loss/gain-of-function analysis were performed to delineate the consequences of WEE2-AS1 upregulation in HCC cells. WEE2-AS1 over-expressed in HCC and was positively correlated to hepatitis B virus (HBV) infection, hepatic vascular invasion, poor tumor differentiation and poor patient prognosis. WEE2-AS1 also accelerated the proliferation, migration, invasion and cell cycle progression of HCC cells. Fermitin family member 3 (FERMT3) was a downstream target of WEE2-AS1. In conclusion, there is a preliminary HBx-WEE2-AS1- FERMT3 pathway which may serve as a therapeutic target for HBV-associated HCC.
Collapse
MESH Headings
- Adult
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Cycle Proteins/antagonists & inhibitors
- Cell Cycle Proteins/genetics
- Cell Cycle Proteins/metabolism
- Cell Line, Tumor
- Cell Movement/genetics
- Cell Proliferation
- Cell Transformation, Neoplastic/genetics
- Female
- Gene Expression Regulation, Neoplastic
- Hepatitis B virus/genetics
- Hepatitis B virus/metabolism
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Male
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Neoplasm Invasiveness/genetics
- Neoplasm Invasiveness/pathology
- Neoplasm Proteins/genetics
- Neoplasm Proteins/metabolism
- Protein-Tyrosine Kinases/antagonists & inhibitors
- Protein-Tyrosine Kinases/genetics
- Protein-Tyrosine Kinases/metabolism
- RNA, Antisense/genetics
- RNA, Antisense/metabolism
- RNA, Long Noncoding/genetics
- RNA, Long Noncoding/metabolism
- Signal Transduction
- Trans-Activators/genetics
- Trans-Activators/metabolism
- Viral Regulatory and Accessory Proteins
Collapse
Affiliation(s)
- Zhigang Hu
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Pinbo Huang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yongcong Yan
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhenyu Zhou
- Guangdong Province Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Research Center of Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jie Wang
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gang Wu
- Department of Hepatobiliary Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
| |
Collapse
|
|
30
|
Van Tong H, Van Ba N, Hoan NX, Binh MT, Quyen DT, Son HA, Van Luong H, Quyet D, Meyer CG, Song LH, Toan NL, Velavan TP. Soluble fibrinogen-like protein 2 levels in patients with hepatitis B virus-related liver diseases. BMC Infect Dis 2018; 18:553. [PMID: 30419833 PMCID: PMC6233598 DOI: 10.1186/s12879-018-3473-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Accepted: 10/31/2018] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Clinical progression of HBV-related liver diseases is largely associated with the activity of HBV-specific T cells. Soluble fibrinogen-like protein 2 (sFGL2), mainly secreted by T cells, is an important effector molecule of the immune system. METHODS sFGL2 levels were determined by ELISA assays in sera of 296 HBV patients clinically classified into the subgroups of acute hepatitis B (AHB), chronic hepatitis B (CHB), liver cirrhosis (LC), hepatocellular carcinoma (HCC) and patients with LC plus HCC. As control group, 158 healthy individuals were included. FGL2 mRNA was quantified by qRT-PCR in 32 pairs of tumor and adjacent non-tumor liver tissues. RESULTS sFGL2 levels were elevated in HBV patients compared to healthy controls (P < 0.0001). In the patient group, sFGL2 levels were increased in AHB compared to CHB patients (P = 0.017). sFGL2 levels were higher in LC patients compared to those without LC (P = 0.006) and were increased according to the development of cirrhosis as staged by Child-Pugh scores (P = 0.024). Similarly, HCC patients had increased sFGL2 levels compared to CHB patients (P = 0.033) and FGL2 mRNA was up-regulated in tumor tissues compared to adjacent non-tumor tissues (P = 0.043). In addition, sFGL2 levels were positively correlated with HBV-DNA loads and AST (Spearman's rho = 0.21, 0.25 and P = 0.006, 0.023, respectively), but reversely correlated with platelet counts and albumin levels (Spearman's rho = - 0.27, - 0.24 and P = 0.014, 0.033, respectively). CONCLUSIONS sFGL2 levels are induced by HBV infection and correlated with the progression and clinical outcome of HBV-related liver diseases. Thus, sFGL2 may serve as a potential indicator for HBV-related liver diseases.
Collapse
Affiliation(s)
- Hoang Van Tong
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam. .,Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam. .,Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.
| | - Nguyen Van Ba
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Nghiem Xuan Hoan
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Mai Thanh Binh
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Dao Thanh Quyen
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Ho Anh Son
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam.,Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Hoang Van Luong
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Do Quyet
- Institute of Biomedicine and Pharmacy, Vietnam Military Medical University, 222 Phung Hung, Ha Dong, Hanoi, Vietnam
| | - Christian G Meyer
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam.,Medical Faculty, Duy Tan University, Da Nang, Vietnam
| | - Le Huu Song
- 108 Military Central Hospital, Hanoi, Vietnam.,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam
| | - Nguyen Linh Toan
- Department of Pathophysiology, Vietnam Military Medical University, Hanoi, Vietnam
| | - Thirumalaisamy P Velavan
- Institute of Tropical Medicine, University of Tübingen, Wilhelmstrasse 27, 72074, Tübingen, Germany. .,Vietnamese-German Center of Excellence in Medical Research, Hanoi, Vietnam. .,Medical Faculty, Duy Tan University, Da Nang, Vietnam.
| |
Collapse
|
|
31
|
Liu H, Li B. The functional role of exosome in hepatocellular carcinoma. J Cancer Res Clin Oncol 2018; 144:2085-2095. [PMID: 30062486 DOI: 10.1007/s00432-018-2712-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide with limited therapeutic options. Exosome is a member of extracellular vesicles that can be released by different cells in liver to communicate with other cells. HCC development has been characterized by a dysfunction of exosome regulation through many molecular mechanisms. The aim of the present review is to summarize the literature on exosomes in HCC, their roles in hepatocarcinogenesis from liver disease, molecules exchange between tumor cells and neighboring cells, metastasis, chemoresistant, immunosuppression, early diagnose and therapy application. METHODS Literatures about HCC and exosomes from PubMed databases were reviewed in this article. RESULTS As our review described, exosomes can induce malignant transformation of liver disease via promoting viral diffusion and inflammation, exchange oncogenic factors between tumor cells, sustain tumor growth by neighboring stromal cells, play a important role in metastasis, trigger chemoresistance through transmitting long noncoding RNAs, stimulate immune activation as well as immune evasion, be utilized in biomarkers discovery and therapeutic options. CONCLUSIONS Available data suggested that exosomes may play an important role in HCC development. More studies on the way that exosomes mediated the HCC progression are needed to promote the clinical utilization of exosomes.
Collapse
Affiliation(s)
- Hongyu Liu
- R&D Department of Guanglian Biomedical Technology (Tianjin) Co., Ltd., Tianjin, 300000, China
| | - Baoguo Li
- Department of Interventional Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
- National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
| |
Collapse
|
|
32
|
Yang Y, Jin L, Tian Z, Guo D, Yao N, Li Q, Jiang Z, Yang D, Tang X, Li H, He Y, Liu J, Chen T, Zhao Y. The association of adverse outcomes in the mother with disease progression in offspring in families with clusters of hepatitis B virus infection and unfavorable prognoses in Northwest China. Medicine (Baltimore) 2018; 97:e12266. [PMID: 30235671 PMCID: PMC6160018 DOI: 10.1097/md.0000000000012266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
To investigate the transmission routes of hepatitis B virus (HBV) in families with clusters of infection and unfavorable prognoses and to analyze the prevalence of liver cirrhosis (LC) or hepatocellular carcinoma (HCC) in the offspring of these families.Families with clusters of HBV infection and unfavorable prognoses were enrolled in the study, and general information and serum samples were collected. The prevalence of LC or HCC was compared in offspring of different genders whose parents were diagnosed with LC or HCC.This analysis comprised 102 probands with 51 siblings, 15 parents, 284 children, and 74 spouses. Interestingly, 88.2% of the siblings and 76.8% of the children of these probands were positive for hepatitis B surface antigen (HBsAg), compared with only 9.5% of the spouses (P < .001). There were 266 nuclear families from 102 clustering families. The prevalence of LC or HCC in sons (44.8%) was higher than that in daughters (8.2%; P < .05) in families with mothers with LC or HCC, but there was no difference in families with fathers with LC or HCC. Moreover, the prevalence of LC or HCC in sons from families with mothers with LC or HCC (44.8%) was higher than in the families with fathers with LC or HCC (21.0%, P = .016).The development of LC or HCC in offspring showed a greater relationship with the adverse outcomes induced by HBV infection in the mother compared with the father, and the prevalence of LC or HCC was much higher in male offspring.
Collapse
Affiliation(s)
- Yuan Yang
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Li Jin
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Zhen Tian
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Dandan Guo
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Naijuan Yao
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Qian Li
- Xian Center for Disease Control and Prevention, Xi’an
| | - Zicheng Jiang
- Department of Infectious Diseases, Ankang City Central Hospital, Ankang, Shaanxi
| | - Daokun Yang
- Department of Infectious Diseases, Xinxiang Medical University, Xinxiang, Henan
| | - Xianmei Tang
- Department of Infectious Diseases, Hanzhong Central Hospital, Hanzhong
| | - Hongbin Li
- Department of Infectious Diseases, Weinan Central Hospital, Weinan, Shaanxi, People's Republic of China
| | - Yingli He
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Jinfeng Liu
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Tianyan Chen
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| | - Yingren Zhao
- Department of Infectious Diseases, First Affiliated Hospital of Xi’an Jiaotong University
| |
Collapse
|
|
33
|
Loglio A, Iavarone M, Grossi G, Viganò M, Rumi MG, Facchetti F, Lunghi G, Sangiovanni A, Colombo M, Lampertico P. Clinical features and outcomes of hepatocellular carcinoma in Caucasian cirrhotic patients on long-term analogue therapy for hepatitis B. Aliment Pharmacol Ther 2018; 48:431-439. [PMID: 29920698 DOI: 10.1111/apt.14848] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 03/02/2018] [Accepted: 05/23/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Long-term oral nucleos(t)ide analogue (NUC) therapy in hepatitis B virus (HBV)-related compensated cirrhotics prevents clinical decompensation but not hepatocellular carcinoma (HCC) development. AIMS To define the clinical features and outcomes of HCC in long-term NUC-treated HBV patients. METHODS All HCCs developing between 2005 and 2016 in NUC-treated HBV patients under surveillance were studied, excluding those that occurred within the first 6 months of therapy. Clinical features of HCC, alpha faetoprotein (AFP) patterns and patients' outcome were studied. RESULTS Seventy-six HCC patients were included. Median age was 67 (40-83) years, 84% males, 96% Caucasian, 95% HBeAg-negative, 96% with undetectable HBV DNA, 83% with normal ALT levels, and 92% with compensated cirrhosis. Median serum AFP levels were 4 (1-3615) ng/mL (>7 ng/mL in 36%). HCC was monofocal in 78%, had a median diameter of 20 (6-57) mm and was in its early stage in 92% which allowed potentially curative treatments in 78% (39% ablation, 28% surgical resection, 11% liver transplantation). Overall, a complete response was obtained in 61 (80%) patients: in 40 after a first-line treatment, in 3 after the second-line treatment, in 2 after the third-line treatment, while 16 underwent liver transplantation (8 as second line). During 45 (7-144) months after HCC diagnosis, 19 patients died, 84% from HCC progression. The median time to recurrence was 20.2 (3-53) months, and the cumulative 5-year liver-related survival was 74%. CONCLUSIONS HCCs developing in patients under long-term NUC treatment were single, small tumours, amenable to curative therapies able to confer excellent 5-year survival rates.
Collapse
Affiliation(s)
- A Loglio
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Iavarone
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - G Grossi
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - M G Rumi
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Milan, Italy
| | - F Facchetti
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - G Lunghi
- Virology Unit, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - A Sangiovanni
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| | - M Colombo
- Center for Translational Hepatology Research, Clinical and Research Center, Humanitas Hospital, Rozzano, Italy
| | - P Lampertico
- CRC "A.M. e A. Migliavacca" Center for the Study of Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy
| |
Collapse
|
|
34
|
Park S, Lim J, Kim JR, Cho S. Inhibitory effects of resveratrol on hepatitis B virus X protein-induced hepatocellular carcinoma. J Vet Sci 2018; 18:419-429. [PMID: 28385009 PMCID: PMC5746434 DOI: 10.4142/jvs.2017.18.4.419] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 01/11/2017] [Accepted: 02/07/2017] [Indexed: 12/27/2022] Open
Abstract
Liver cancer occurs very frequently worldwide and hepatocellular carcinoma (HCC) accounts for more than 80% of total primary liver cancer cases. In this study, the anticarcinogenic effects of resveratrol against hepatitis B virus (HBV)-induced HCC were investigated by using HBV X-protein-overexpressing Huh7 (Huh7-HBx) human hepatoma cells. MTT assay showed that resveratrol decreased cell viability. Fluorescence-activated cell-sorter analysis showed that resveratrol induced G1 cell cycle arrest without increasing the sub-G1 phase cell population. Therefore, we evaluated its effect on regulation of cyclin D1, which is critically involved in G1/S transition. Resveratrol lowered cyclin D1 transcription. Western blot analysis of the effects of resveratrol on upstream cyclin D1 transcriptional signaling, extracellular signal-related kinase (ERK), p90RSK, Akt, and p70S6K revealed inhibition of Akt but not the ERK signaling pathway. Collectively, the results indicate that resveratrol inhibits Huh7-HBx proliferation by decreasing cyclin D1 expression through blockade of Akt signaling. We investigated the anticarcinogenic effect and mechanism of resveratrol in xenograft model mice implanted with Huh7-HBx cells. Intraperitoneal resveratrol injection reduced tumor size in the mice. Expression of survivin was reduced, but cyclin D1 was not affected. The results demonstrate that resveratrol treatment may help manage HBV-induced HCC by regulating survivin.
Collapse
Affiliation(s)
- Seungmo Park
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.,Institute of Laboratory Animal Resources, Seoul National University, Seoul 08826, Korea
| | - Jihae Lim
- College of Pharmacy, Seoul National University, Seoul 08826, Korea
| | - Jong Rhan Kim
- Advanced Institutes of Convergence Technology, Seoul National University, Seoul 08826, Korea
| | - Seongbeom Cho
- BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| |
Collapse
|
|
35
|
Chung YL, Wu ML. The Role of Promyelocytic Leukemia Protein in Steatosis-Associated Hepatic Tumors Related to Chronic Hepatitis B virus Infection. Transl Oncol 2018; 11:743-754. [PMID: 29684791 PMCID: PMC6050444 DOI: 10.1016/j.tranon.2018.03.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2017] [Revised: 03/29/2018] [Accepted: 03/29/2018] [Indexed: 02/08/2023] Open
Abstract
The persistence of hepatitis B surface antigen (HBsAg) is a risk factor for the development of steatosis-associated tumors in chronic hepatitis B virus (HBV) infection, yet little is known about the metabolic link with this factor. We correlated HBV-related pathogenesis in genetically engineered mice and human carriers with metabolic proteomics and lipogenic gene expression profiles. The immunohistochemistry showed that the promyelocytic leukemia protein (PML, a tumor suppressor involved in genome maintenance and fatty acid oxidation), being inversely influenced by the dynamic HBsAg levels from acute phase to seroclearance, appeared as a lipo-metabolic switch linking HBsAg-induced steatosis (lipogenesis) to HBsAg-lost fat-burning hepatocarcinogenesis (lipolysis). Knockdown of PML in HBsAg-transgenic mice predisposed to obesity and drove early steatosis-specific liver tumorigenesis. Proteome analysis revealed that the signaling pathways corresponding to energy metabolism and its regulators were frequently altered by suppression or depletion of PML in the HBsAg-transgenic mice, mainly including oxidative phosphorylation and fatty acid metabolism. Expression profiling further identified upregulation of stearoyl-CoA desaturase 1 (Scd1) and epigenetic methylation of NDUFA13 in the mitochondrial respiratory chain and the cell cycle inhibitor CDKN1c in concordance to the increased severity of lipodystrophy and neoplasia in the livers of HBsAg-transgenic mice with PML insufficiency. The defect in lipolysis in PML-deficient HBsAg-transgenic mice made the HBsAg-induced adipose-like liver tumors vulnerable to synthetic lethality from toxic saturated fat accumulation with a Scd1 inhibitor. Our findings provide mechanistic insights into the evolution of steatosis-associated hepatic tumors driven by reciprocal interactions of HBsAg and PML, and a potential utility of lipid metabolic reprogramming as a treatment target.
Collapse
Affiliation(s)
- Yih-Lin Chung
- Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei 112, Taiwan.
| | - Mei-Ling Wu
- Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei 112, Taiwan
| |
Collapse
|
|
36
|
Wang Y, Wang H, Pan S, Hu T, Shen J, Zheng H, Xie S, Xie Y, Lu R, Guo L. Capable Infection of Hepatitis B Virus in Diffuse Large B-cell Lymphoma. J Cancer 2018; 9:1575-1581. [PMID: 29760795 PMCID: PMC5950586 DOI: 10.7150/jca.24384] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 02/08/2018] [Indexed: 01/05/2023] Open
Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common pathological type of non-Hodgkin lymphoma (NHL). It is strongly correlated to the host immunity and infection status. Aim: This study tested the hypothesis that hepatitis B virus (HBV) infection is also associated with DLBCL. Methods: Clinical analysis of the correlation between DLBCL and HBV infection, detection of HBV in situ of DLBCL tissue, and biological experiments that determined whether HBV infects B lymphocytes were conducted. Results: Our long-term clinical data showed that the positive rate of serum HBV was significantly increased in DLBCL patients (23.6%) compared to that in the general Chinese population (7.2%, P<0.001), especially in advanced stage lymphoma patients (P=0.003). In addition, HBV could infect B lymphocytes in vitro and the HBV antigen and nucleic acid could be detected intracellularly. Hepatitis B x protein (HBx) was also strongly expressed in tissues from DLBCL patients that were serum HBV surface antigen (HBsAg) positive. These patients responded less well to therapy with an odds ratio (OR) of 3.04. Conclusions: HBV can infect B lymphocytes. It might be related to the development of DLBCL and may also impact the efficacy of treatment.
Collapse
Affiliation(s)
- Yanchun Wang
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Huijie Wang
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.,Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shaokun Pan
- Department of Pathogen Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Tao Hu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiabin Shen
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Hui Zheng
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Suhong Xie
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Youhua Xie
- Department of Pathogen Biology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| |
Collapse
|
|
37
|
Shin JG, Cheong HS, Kim JY, Lee JH, Yu SJ, Yoon JH, Cheong JY, Cho SW, Park NH, Namgoong S, Kim LH, Kim YJ, Shin HD. Identification of additional EHMT2 variant associated with the risk of chronic hepatitis B by GWAS follow-up study. Genes Immun 2017; 20:1-9. [PMID: 29238036 DOI: 10.1038/s41435-017-0004-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 07/12/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B (CHB) is a precursor to liver cirrhosis and hepatocellular carcinoma, caused by a Hepatitis B viral infection. Genome-wide association studies (GWASs) have been conducted to find genes associated with CHB risk. In previous GWAS, EHMT2 was identified as one of the susceptibility genes for CHB. To further characterize this association and discover possible causal variants, we conducted an additional association study. A total of 11 EHMT2 single-nucleotide polymorphisms (SNP) were selected and genotyped in 3902 subjects (1046 CHB patients and 2856 controls). An additional eight imputed SNPs were also included in further analysis. As a result, rs35875104 showed a strong association with the CHB, along with the previously reported genetic marker for CHB risk, rs652888 (odds ratio (OR) = 0.53, P = 2.20 × 10-8 at rs35875104 and OR = 1.58, P = 9.90 × 10-12 at rs652888). In addition, linkage disequilibrium and conditional analysis identified one SNP (rs35875104) as a novel genetic marker for CHB susceptibility. The GRSs (genetic risk scores) were calculated to visualize the combined genetic effects of all known CHB-associated loci, including EHMT2 rs35875104, which was additionally identified in this study. The findings from the present study may be useful for further understanding of the genetic etiology of CHB.
Collapse
Affiliation(s)
- Joong-Gon Shin
- Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea.,Research Institute for Basic Science, Sogang University, Seoul, 121-742, Republic of Korea
| | - Hyun Sub Cheong
- Department of Genetic Epidemiology, SNP Genetics, Sogang University, Inc., Taihard building 1007, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea
| | - Jason Yongha Kim
- Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University, 28 Yungun-dong, Chongro-Gu, Seoul, 110-744, Republic of Korea
| | - Su Jong Yu
- Department of Internal Medicine and Liver Research Institute, Seoul National University, 28 Yungun-dong, Chongro-Gu, Seoul, 110-744, Republic of Korea
| | - Jung-Hwan Yoon
- Department of Internal Medicine and Liver Research Institute, Seoul National University, 28 Yungun-dong, Chongro-Gu, Seoul, 110-744, Republic of Korea
| | - Jae Youn Cheong
- Department of Internal Medicine, Seoul National University Boramae Medical Center, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul, 156-707, Republic of Korea
| | - Sung Won Cho
- Department of Gastroenterology, Ajou University School of Medicine, San-5 Wonchon-dong, Youngtong-gu, Suwon, 442-721, Republic of Korea
| | - Neung Hwa Park
- Department of Internal Medicine, Ulsan University Hospital, 877 Bangeojin Sunhwan-doro, Dong-gu, Ulsan, 682-714, Republic of Korea
| | - Suhg Namgoong
- Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea.,Department of Genetic Epidemiology, SNP Genetics, Sogang University, Inc., Taihard building 1007, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea
| | - Lyoung Hyo Kim
- Department of Genetic Epidemiology, SNP Genetics, Sogang University, Inc., Taihard building 1007, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea
| | - Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University, 28 Yungun-dong, Chongro-Gu, Seoul, 110-744, Republic of Korea.
| | - Hyoung Doo Shin
- Department of Life Science, Sogang University, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea. .,Research Institute for Basic Science, Sogang University, Seoul, 121-742, Republic of Korea. .,Department of Genetic Epidemiology, SNP Genetics, Sogang University, Inc., Taihard building 1007, 1 Shinsu-dong, Mapo-gu, Seoul, 121-742, Republic of Korea.
| |
Collapse
|
|
38
|
Dandri M, Petersen J. Mechanism of Hepatitis B Virus Persistence in Hepatocytes and Its Carcinogenic Potential. Clin Infect Dis 2017; 62 Suppl 4:S281-8. [PMID: 27190317 DOI: 10.1093/cid/ciw023] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Liver disease associated with persistent infection with hepatitis B virus (HBV) continues to be a major health problem of global impact. Despite the existence of an effective vaccine, at least 240 million people are chronically infected worldwide, and are at risk of developing liver cirrhosis and hepatocellular carcinoma. Although chronic HBV infection is considered the main risk factor for liver cancer development, the molecular mechanisms determining persistence of infection and long-term pathogenesis are not fully elucidated but appear to be multifactorial. Current therapeutic regimens based on the use of polymerase inhibitors can efficiently suppress viral replication but are unable to eradicate the infection. This is due both to the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA), in the nucleus of infected hepatocytes, as well as to the inability of the immune system to efficiently counteract chronic HBV infection. In this regard, the unique replication strategies adopted by HBV and viral protein production also appear to contribute to infection persistence by limiting the effectiveness of innate responses. The availability of improved experimental systems and molecular techniques have started to provide new information about the complex network of interactions that HBV establishes within the hepatocyte and that may contribute to disease progression and tumor development. Thus, this review will mostly focus on events involving the hepatocyte: the only target cell where HBV infection and replication take place.
Collapse
Affiliation(s)
- Maura Dandri
- I Department of Internal Medicine, University Medical Center Hamburg-Eppendorf German Center for Infection Research, Hamburg-Lübeck-Borstel site
| | - Joerg Petersen
- IFI Institute for Interdisciplinary Medicine, Asklepios Clinic St Georg, Hamburg, Germany
| |
Collapse
|
|
39
|
Enomoto Y, Takagi R, Naito Y, Kiniwa T, Tanaka Y, Hamada-Tsutsumi S, Kawano M, Matsushita S, Ochiya T, Miyajima A. Identification of the novel 3' UTR sequences of human IL-21 mRNA as potential targets of miRNAs. Sci Rep 2017; 7:7780. [PMID: 28798470 PMCID: PMC5552845 DOI: 10.1038/s41598-017-07853-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 06/30/2017] [Indexed: 12/18/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma worldwide. However, the strategy of HBV to escape from the host immune system remains largely unknown. In this study, we examined extracellular vesicles (EVs) secreted from human hepatocytes infected with HBV. EVs includeing exosomes are nano-size vesicles with proteins, mRNAs, and microRNAs (miRNAs), which can be transmitted to different cells. We found that 104 EV associated miRNAs were increased in hepatocytes more than 2-fold by HBV infection. We then selected those that were potentially implicated in immune regulation. Among them, five HBV-induced miRNAs were found to potentially target multiple sequences in the 3'UTR of IL-21, a cytokine that induces anti-viral immunity. Moreover, expression of a reporter gene with the 3' UTR of human IL-21 mRNA was suppressed by the five miRNAs individually. Finally, IL-21 expression in cloned human T cells was down-regulated by the five miRNAs. Collectively, this study identified the novel 3' UTR sequences of human IL-21 mRNA and potential binding sites of HBV-induced EV-miRNAs.
Collapse
Affiliation(s)
- Yutaka Enomoto
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
| | - Rie Takagi
- Department of Allergy and Immunology Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Yutaka Naito
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tsuyoshi Kiniwa
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Susumu Hamada-Tsutsumi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-ku, Nagoya, 467-8601, Japan
| | - Masaaki Kawano
- Department of Allergy and Immunology Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Sho Matsushita
- Department of Allergy and Immunology Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan.
| |
Collapse
|
|
40
|
Xu W, Yu J, Wong VWS. Mechanism and prediction of HCC development in HBV infection. Best Pract Res Clin Gastroenterol 2017; 31:291-298. [PMID: 28774411 DOI: 10.1016/j.bpg.2017.04.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Accepted: 04/28/2017] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B virus (HBV) infection remains one of the leading causes of hepatocellular carcinoma (HCC) globally. Over the past few decades, the risk factors of HCC in patients with chronic hepatitis B have been well characterized, and can be divided into host and viral factors. A few groups have also derived and validated HCC prediction scores based on these risk factors. In general, the scores have high negative predictive value in identifying a low risk group who may not need HCC surveillance in the next 3-5 years. The scores have been tested originally in Asian patients, and results on their performance in the Caucasian population are conflicting. Furthermore, new research has identified genetic factors and new virological markers (e.g. hepatitis B surface antigen and core-related antigen levels) for HCC, but they are yet to be applied in routine clinical practice.
Collapse
Affiliation(s)
- Weiqi Xu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Vincent Wai-Sun Wong
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong; Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.
| |
Collapse
|
|
41
|
Zamor PJ, deLemos AS, Russo MW. Viral hepatitis and hepatocellular carcinoma: etiology and management. J Gastrointest Oncol 2017; 8:229-242. [PMID: 28480063 DOI: 10.21037/jgo.2017.03.14] [Citation(s) in RCA: 104] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) and chronic hepatitis C virus (HCV) are associated with hepatic fibrosis and development of hepatocellular carcinoma (HCC). There are differences and variation with the incidence of HCC worldwide. Additionally, HCC develops via different pathways with these viral hepatitides. This review outlines the various mechanisms and pathophysiology that contributes to this process. There will also be a review on the recommended screening for HCC. Treatment considerations, which are different for these viruses, will be outlined in this review.
Collapse
Affiliation(s)
- Philippe J Zamor
- Division of Hepatology, Carolinas Medical Center, Charlotte, USA
| | - Andrew S deLemos
- Division of Hepatology, Carolinas Medical Center, Charlotte, USA
| | - Mark W Russo
- Division of Hepatology, Carolinas Medical Center, Charlotte, USA
| |
Collapse
|
|
42
|
Wang M, Xi D, Ning Q. Virus-induced hepatocellular carcinoma with special emphasis on HBV. Hepatol Int 2017; 11:171-180. [PMID: 28097530 DOI: 10.1007/s12072-016-9779-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Accepted: 12/22/2016] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is a common malignant tumor with high lethality, and the hepatitis B virus (HBV) is a chief cause. HBV can accelerate HCC via multiple mechanisms. First, HBV induces immune reactions that lead to repeated hepatic inflammation, fibrosis and a deficient immune microenvironment. Subsequently, HBV can modify host genes near the insertion point through DNA integration to cause host cell genome instability and to generate carcinogenic fusion proteins. Additionally, HBV expresses diverse active proteins, especially HBx and HBs, which have a range of transactivation functions such as regulation of apoptosis, interference with intracellular signaling pathways, and alteration of epigenetics. Currently, primary prevention measures for HBV-induced HCC focus on vaccination and antiviral treatment. Here, we report the epidemiology, the molecular mechanism and the progress in therapeutic strategies for controlling HBV-induced HCC.
Collapse
Affiliation(s)
- Ming Wang
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Dong Xi
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No 1095, Jiefang Avenue, Wuhan, 430030, China
| | - Qin Ning
- Department of Infectious Disease, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, No 1095, Jiefang Avenue, Wuhan, 430030, China.
| |
Collapse
|
|
43
|
Guerrieri F, Belloni L, D'Andrea D, Pediconi N, Le Pera L, Testoni B, Scisciani C, Floriot O, Zoulim F, Tramontano A, Levrero M. Genome-wide identification of direct HBx genomic targets. BMC Genomics 2017; 18:184. [PMID: 28212627 PMCID: PMC5316204 DOI: 10.1186/s12864-017-3561-5] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 02/07/2017] [Indexed: 02/08/2023] Open
Abstract
Background The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV. Results ChIP-Seq high throughput sequencing of HBx-bound fragments was used to obtain a high-resolution, unbiased, mapping of HBx binding sites across the genome in HBV replicating cells. Protein-coding genes and ncRNAs involved in cell metabolism, chromatin dynamics and cancer were enriched among HBx targets together with genes/ncRNAs known to modulate HBV replication. The direct transcriptional activation of genes/miRNAs that potentiate endocytosis (Ras-related in brain (RAB) GTPase family) and autophagy (autophagy related (ATG) genes, beclin-1, miR-33a) and the transcriptional repression of microRNAs (miR-138, miR-224, miR-576, miR-596) that directly target the HBV pgRNA and would inhibit HBV replication, contribute to HBx-mediated increase of HBV replication. Conclusions Our ChIP-Seq analysis of HBx genome wide chromatin recruitment defined the repertoire of genes and ncRNAs directly targeted by HBx and led to the identification of new mechanisms by which HBx positively regulates cccDNA transcription and HBV replication. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3561-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Francesca Guerrieri
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy
| | - Laura Belloni
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy
| | - Daniel D'Andrea
- Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy
| | - Natalia Pediconi
- Department of Molecular Medicine, Sapienza University, Viale Regina Elena 291, Rome, 00161, Italy
| | - Loredana Le Pera
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy.,Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy
| | - Barbara Testoni
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Cecilia Scisciani
- Department of Internal Medicine - DMISM, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy
| | - Oceane Floriot
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Fabien Zoulim
- INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France
| | - Anna Tramontano
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy.,Biocomputing Lab, Department of Physics, Sapienza University, Rome, Italy.,Istituto Pasteur Fondazione Cenci Bolognetti, Viale Regina Elena 291, Rome, 00161, Italy
| | - Massimo Levrero
- Center for Life NanoScience@Sapienza, Istituto Italiano di Tecnologia, Viale Regina Elena 291, Rome, 00161, Italy. .,INSERM U1052, Cancer Research Center of Lyon (CRCL), 151 cours Albert Thomas, Lyon, 69424, France. .,Department of Internal Medicine - DMISM, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy. .,Cancer Research Center of Lyon (CRCL) - INSERM U1052, 151 cours Albert Thomas, 69424, Lyon Cedex 03, France.
| |
Collapse
|
|
44
|
Hepatitis B virus X protein is capable of down-regulating protein level of host antiviral protein APOBEC3G. Sci Rep 2017; 7:40783. [PMID: 28098260 PMCID: PMC5241686 DOI: 10.1038/srep40783] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 12/09/2016] [Indexed: 12/17/2022] Open
Abstract
The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family proteins bind RNA and single-stranded DNA, and create C-to-U base modifications through cytidine deaminase activity. APOBEC3G restricts human immunodeficiency virus 1 (HIV-1) infection by creating hypermutations in proviral DNA, while HIV-1-encoded vif protein antagonizes such restriction by targeting APOBEC3G for degradation. APOBEC3G also inhibits hepatitis B virus (HBV): APOBEC3G co-expression inhibits HBV replication and evidences exist indicating APOBEC3G-mediated HBV hypermutations in patients. HBV encodes a small non-structural X protein (HBx) with a recognized activating effect on HBV life cycle. In this work, we report the discovery that HBx selectively and dose-dependently decreases the protein level of co-expressed APOBEC3G in transfected Huh-7 cells. The effect was shown to take place post-translationally, but does not rely on protein degradation via proteasome or lysosome. Further work demonstrated that intracellular APOBEC3G is normally exported via exosome secretion and inhibition of exosome biogenesis causes retention of intracellular APOBEC3G. Finally, HBx co-expression specifically enhanced externalization of APOBEC3G via exosomes, resulting in decrease of intracellular APOBEC3G protein level. These data suggest the possibility that in addition to other mechanisms, HBx-mediated activation of HBV might also involve antagonizing of intracellular restriction factor APOBEC3G through promotion of its export.
Collapse
|
|
45
|
Zhang C, Li H, Jiang W, Zhang X, Li G. Icaritin inhibits the expression of alpha-fetoprotein in hepatitis B virus-infected hepatoma cell lines through post-transcriptional regulation. Oncotarget 2016; 7:83755-83766. [PMID: 27835879 PMCID: PMC5347802 DOI: 10.18632/oncotarget.13194] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 10/21/2016] [Indexed: 12/30/2022] Open
Abstract
Although it has showed that icaritin can apparently suppress growth of HCC by reducing the level of AFP, the intrinsic mechanism remains unclear. In this study, we explored the possible mechanism of miRNAs on post-transcriptional regulation of AFP gene, as well as the effects of HBV infection and icaritin in hepatoma cells. The results showed that miR-620, miR-1236 and miR-1270 could bind target sites in the range of 9-18 nt and 131-151 nt downstream of the stop codon in the AFP mRNA 3'-UTR to suppress the expression of AFP. Mutation of these target sites could reverse the effects of these miRNAs. Icaritin (10 μM) might reduce the stability and translational activity of AFP mRNA by increasing the expression levels of these mentioned miRNAs. HBV infection resulted in apparent decreases of these miRNAs and, consequently, increased AFP expression. The results indicated that miR-620, miR-1236 and miR-1270 are critical factors in the post-transcriptional regulation of AFP. Icaritin can counteract the effect of HBV. These findings will contribute to full understanding of the regulatory mechanism of AFP expression in hepatoma cells. And also it revealed a synergistic mechanism of HBV infection and elevation of AFP in the pathogenesis of HCC, as well as the potential clinical significance of icaritin on the therapy of HCC induced by HBV.
Collapse
Affiliation(s)
- Chao Zhang
- Department of Cell Biology and Municipal Laboratory of Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Wei Jiang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Xiaowei Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Gang Li
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| |
Collapse
|
|
46
|
Rogler CE, Bebawee R, Matarlo J, Locker J, Pattamanuch N, Gupta S, Rogler LE. Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver. J Histochem Cytochem 2016; 65:33-46. [PMID: 27879410 DOI: 10.1369/0022155416675153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have reported many markers associated with human liver stem/progenitor cells, "oval cells," and identified "niches" in diseased livers where stem cells occur. However, there has remained a need to identify entire lineages of stem cells as they differentiate into bile ducts or hepatocytes. We have used combined immunohistochemical staining for a marker of hepatic commitment and specification (FOXA2 [Forkhead box A2]), hepatocyte maturation (Albumin and HepPar1), and features of bile ducts (CK19 [cytokeratin 19]) to identify lineages of stem cells differentiating toward the hepatocytic or bile ductular compartments of end-stage cirrhotic human liver. We identified large clusters of disorganized, FOXA2 expressing, oval cells in localized liver regions surrounded by fibrotic matrix, designated as "micro-niches." Specific FOXA2-positive cells within the micro-niches organize into primitive duct structures that support both hepatocytic and bile ductular differentiation enabling identification of entire lineages of cells forming the two types of structures. We also detected expression of hsa-miR-122 in primitive ductular reactions expected for hepatocytic differentiation and hsa-miR-23b cluster expression that drives liver cell fate decisions in cells undergoing lineage commitment. Our data establish the foundation for a mechanistic hypothesis on how stem cell lineages progress in specialized micro-niches in cirrhotic end-stage liver disease.
Collapse
Affiliation(s)
- Charles E Rogler
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Genetics (CER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Microbiology and Immunology (CER), Albert Einstein College of Medicine, Bronx, New York
| | - Remon Bebawee
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
| | - Joe Matarlo
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
| | - Joseph Locker
- Division of Molecular Anatomic Pathology, Department of Pathology, University of Pittsburg, Pittsburg, Pennsylvania (JL)
| | - Nicole Pattamanuch
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Montefiore Medical Center, Bronx, New York (NP)
| | - Sanjeev Gupta
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Pathology (SG), Albert Einstein College of Medicine, Bronx, New York
| | - Leslie E Rogler
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
| |
Collapse
|
|
47
|
Abstract
Chronic hepatitis B infection (CHB) is a known risk factor for malignancy. Unlike hepatocellular carcinoma (HCC), less is known about the risk of non-HCC malignancy. However, epidemiology and pathologic evidence suggests a strong association between non-Hodgkin lymphoma and CHB. Data regarding the risk of other malignancies, such as pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma, are mixed. Surveillance and appropriate treatment of infection and malignancy in these patients is essential. Further study of these associations is needed and may bring new insights in the pathogenesis and treatment of these diseases.
Collapse
Affiliation(s)
- Ryan M Kwok
- Gastroenterology Fellowship Program, Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda, MD 20889, USA.
| | - Tram T Tran
- Gastroenterology Fellowship Program, Cedars Sinai Medical Center, Geffen School of Medicine at University of California Los Angeles, 8900 Beverly Boulevard, Los Angeles, CA 90048, USA
| |
Collapse
|
|
48
|
Coleman OI, Nunes T. Role of the Microbiota in Colorectal Cancer: Updates on Microbial Associations and Therapeutic Implications. Biores Open Access 2016; 5:279-288. [PMID: 27790385 PMCID: PMC5076480 DOI: 10.1089/biores.2016.0028] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Genetic, environmental, and dietary factors have been found to influence the development and progression of colorectal cancer (CRC). More recently, accumulating evidence associates the intestinal microbiota with the initiation and progression of this disease. While studies have shown that individuals with CRC display alterations in gut bacterial composition, it remains somewhat unclear whether such differences drive cancer development or whether they are a response to tumorigenesis. In this review, the authors assess new evidence linking the community structure or specific bacterial factors of the intestinal microbiota to CRC development and progression, with insights into therapeutic implications.
Collapse
Affiliation(s)
- Olivia I Coleman
- Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Technical University of Munich , Freising, Germany
| | - Tiago Nunes
- Chair of Nutrition and Immunology, ZIEL-Research Center for Nutrition and Food Sciences, Technical University of Munich , Freising, Germany
| |
Collapse
|
|
49
|
Rhee H, Nahm JH, Kim H, Choi GH, Yoo JE, Lee HS, Koh MJ, Park YN. Poor outcome of hepatocellular carcinoma with stemness marker under hypoxia: resistance to transarterial chemoembolization. Mod Pathol 2016; 29:1038-49. [PMID: 27312064 DOI: 10.1038/modpathol.2016.111] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 05/06/2016] [Accepted: 05/06/2016] [Indexed: 12/12/2022]
Abstract
Hypoxia is known to be important in the generation and maintenance of stemness; however, its clinical significance is yet to be determined in human hepatocellular carcinoma. The expression of stemness (K19, EpCAM) and hypoxia (carbonic anhydrase-IX (CAIX))-related markers were investigated by immunohistochemistry in three hepatocellular carcinoma cohorts. The clinicopathologic features, response to transarterial chemoembolization, and outcomes were compared. In cohort 1 (n=14, biopsy-transarterial chemoembolization-resection-matched hepatocellular carcinoma), all K19-, EpCAM-, or CAIX-positive hepatocellular carcinomas on initial biopsy (6/6, 100%) showed residual tumors after transarterial chemoembolization, whereas 75% (6/8) of all-negative hepatocellular carcinomas on biopsy showed complete necrosis in the post-transarterial chemoembolization-resected specimens. In cohort 2 (n=85, explanted hepatocellular carcinomas with/without transarterial chemoembolization; totally necrotic hepatocellular carcinoma after transarterial chemoembolization was not included), the expression of K19, EpCAM, and CAIX, and their coexpression, was more frequently observed with a greater number of transarterial chemoembolization sessions, and the expression of these markers was also correlated to each other. CAIX expression was shown to be an independent factor for recurrence and survival, and combination of CAIX with Milan criteria significantly increased the time-dependent integrative area under the curve values for recurrence and survival. In cohort 3 (n=339, resected hepatocellular carcinomas without transarterial chemoembolization), CAIX(+) hepatocellular carcinomas exhibited higher K19 and EpCAM expression, and more invasive pathological features. CAIX expression and TNM stage were independent predictors of extrahepatic recurrence, and the addition of CAIX to the TNM stage significantly increased time-dependent integrative area under the curve values. In conclusion, the expression of stemness (K19, EpCAM) and hypoxia (CAIX)-related markers were correlated each other, and hepatocellular carcinoma expressing these markers showed resistance to transarterial chemoembolization and poorer outcome. Evaluation for both markers of stemness and hypoxia may have an additional value in predicting hepatocellular carcinoma outcome, especially for transarterial chemoembolization-treated hepatocellular carcinomas.
Collapse
Affiliation(s)
- Hyungjin Rhee
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hae Nahm
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Department of Research Affairs, Yonsei University College of Medicine, Seoul, Korea
| | - Myoung Ju Koh
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.,Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
| |
Collapse
|
|
50
|
Nishikawa H, Nishijima N, Enomoto H, Sakamoto A, Nasu A, Komekado H, Nishimura T, Kita R, Kimura T, Iijima H, Nishiguchi S, Osaki Y. A predictive model for carcinogenesis in patients with chronic hepatitis B undergoing entecavir therapy and its validation. Medicine (Baltimore) 2016; 95:e4832. [PMID: 27603400 PMCID: PMC5023923 DOI: 10.1097/md.0000000000004832] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Revised: 07/27/2016] [Accepted: 08/16/2016] [Indexed: 02/07/2023] Open
Abstract
We created a model to predict the development of liver carcinogenesis in patients with chronic hepatitis B (CHB) undergoing entecavir (ETV) therapy and to validate the accuracy using an independent dataset.A total of 328 CHB subjects were analyzed. Subjects were randomly assigned into 2 groups: the training group (n = 164) and the validation group (n = 164). Using data from the training group, we built a predictive model for liver carcinogenesis by performing univariate and multivariate analyses using variables associated with liver carcinogenesis. We subsequently assessed the applicability of the constructed model in the validation group.The median (range) follow-up periods in the training and the validation groups were 5.03 years (1.03-9.98) and 4.84 years (1.10-9.97), respectively. The proportion of hepatitis B virus-DNA at 24 weeks <1.9 log IU/mL in the training group was 70.7% (116/164), while that in the validation group was 71.3% (117/164). For the entire cohort (n = 328), the median alpha-fetoprotein (AFP) value at 24 weeks (3.45 ng/mL; range, 0.9-102.7 ng/mL) significantly decreased compared to the baseline values (5.55 ng/mL; range, 0.9-1039.5 ng/mL), while the median alanine aminotransferase (ALT) value at 24 weeks (24 IU/mL; range, 6-251 IU/mL) also significantly decreased compared to baseline values (57 IU/mL; range, 7-1450 IU/mL). During the observation period, hepatocellular carcinoma (HCC) developed in 15 (9.1%) patients in the training group and in 17 (10.4%) patients in the validation group. The 3- and 5-year cumulative HCC incidence rates in the entire cohort were 4.48% and 9.52%, respectively. In the multivariate analysis of the training group, age ≥54 years (P = 0.0273), ALT level at 24 weeks (P = 0.0456), and AFP at 24 weeks (P = 0.0485) were found to be significant predictors linked to HCC. Using these independent predictors, the risk for HCC development was well stratified in the validation group (overall significance, P < 0.0001). Similar results were observed in subgroup analyses of patients with or without cirrhosis and HBe antigen positivity.In conclusion, our predictive model was well verified; hence, it may be a promising model for the prediction of the development of liver carcinogenesis in CHB patients undergoing ETV therapy.
Collapse
Affiliation(s)
- Hiroki Nishikawa
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo
| | - Norihiro Nishijima
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Hirayuki Enomoto
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo
| | - Azusa Sakamoto
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Akihiro Nasu
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Hideyuki Komekado
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Takashi Nishimura
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo
| | - Ryuichi Kita
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Toru Kimura
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| | - Hiroko Iijima
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo
| | - Yukio Osaki
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, Osaka Prefecture, Japan
| |
Collapse
|