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Maekawa S, Takano S, Enomoto N. Risk of hepatocellular carcinoma after viral clearance achieved by DAA treatment. J Formos Med Assoc 2024; 123:1124-1130. [PMID: 38245398 DOI: 10.1016/j.jfma.2024.01.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/18/2023] [Accepted: 01/09/2024] [Indexed: 01/22/2024] Open
Abstract
The advent of direct-acting antiviral (DAA) therapy has revolutionized hepatitis C virus (HCV) treatment, enabling most HCV-infected patients to achieve a sustained viral response (SVR) easily and safely in a short period. On the other hand, it is gradually being recognized that a significant proportion of patients are still at risk of developing de novo and recurrent hepatocellular carcinoma (HCC), even after HCV elimination, and therefore, elucidation of the risk of de novo and recurrent HCC, investigation of its molecular basis, and construction of accurate prediction models are emerging as new important clinical topics. In this review, we present recent advances regarding these issues.
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Affiliation(s)
- Shinya Maekawa
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.
| | - Shinichi Takano
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Nobuyuki Enomoto
- Department of Gastroenterology and Hepatology, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
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Shou J, Zhang C, Zheng X, Li Y, Wu P, Chen L, Wei X. LncRNA HCP5 Facilitates the Progression of Ovarian Cancer by Interacting with the PTBP1 Protein. Biochem Genet 2024; 62:3136-3154. [PMID: 38071681 PMCID: PMC11289333 DOI: 10.1007/s10528-023-10558-8] [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: 07/14/2023] [Accepted: 10/22/2023] [Indexed: 07/31/2024]
Abstract
Ovarian cancer (OC) is a major gynecological malignancy with an annually increasing morbidity that poses a significant threat to the health of women worldwide. Most OC patients are diagnosed at an advanced stage. It is an urgent task to search for biomarkers for the diagnosis and treatment of OC. The lncRNA HCP5 (HCP5) was recently identified as an oncogene in several malignant tumors. However, the function of HCP5 in OC has rarely been reported. Herein, the levels of HCP5 and PTBP1 were found to be markedly increased in malignant OC tumor tissues and OC cell lines. In HCP5-silenced SKOV-3 and HEY cells, cell viability was markedly decreased, and the apoptosis rate was significantly increased, with more cells exhibiting G0/G1 arrest and increased expression of cleaved caspase-3 and cleaved caspase-9. Furthermore, the number of migrated cells, number of invaded cells, and migration distance were notably decreased by the knockdown of HCP5 in SKOV-3 cells and HEY cells. In the xenograft model established with SKOV-3 cells, the number of lung metastases, tumor growth, and Ki67 expression in tumor tissues were markedly decreased by the knockdown of HCP5, accompanied by an increased percentage of TUNEL-positive cells. HCP5 was found to be localized in the nucleus, and the interaction between HCP5 and PTBP1 was verified by RNA pull-down and RNA immunoprecipitation assays. Furthermore, in HCP5-overexpressing OC cells, the impacts of HCP5 on cell proliferation and apoptosis were significantly attenuated by the knockdown of PTBP1. Collectively, these results indicate that HCP5 facilitates the progression of OC by interacting with the PTBP1 protein.
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Affiliation(s)
- Jian Shou
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - Chuanling Zhang
- Department of Translational Medicine Laboratory, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - Xiaoyu Zheng
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - Yaowei Li
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - Peng Wu
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - Long Chen
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China
| | - XiuJun Wei
- Department of Gynecology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, No. 728, North Yucai Road, Beigan Street, Xiaoshan District, Hangzhou, 311200, Zhejiang, China.
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Correlation of DEPDC5 rs1012068 and rs5998152 Polymorphisms with Risk of Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis. JOURNAL OF ONCOLOGY 2023; 2023:5957481. [PMID: 36733671 PMCID: PMC9889158 DOI: 10.1155/2023/5957481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 12/23/2022] [Accepted: 01/04/2023] [Indexed: 01/25/2023]
Abstract
Background Emerging evidence has shown that two common genetic polymorphisms within the pleckstrin domain-containing protein 5 (DEPDC5), rs1012068 and rs5998152, may be associated with the risk of hepatocellular carcinoma (HCC), especially in those individuals chronically infected with the hepatitis C virus (HCV) or the hepatitis B virus (HBV). However, these findings have not been consistently replicated in the literature due to limited sample sizes or different etiologies of HCC. Thus, the present systematic review and meta-analysis were performed to resolve this inconsistency. Methods The databases PubMed, Embase, Web of Science, the China National Knowledge Infrastructure, and Scopus were searched up to December 12, 2022. Data from relevant studies were pooled, and odds ratios and 95% confidence intervals were calculated. Results A total of 11 case-control studies encompassing 2,609 cases and 8,171 controls on rs1012068 and three encompassing 411 cases and 1,448 controls on rs5998152 were included. Results indicated that the DEPDC5 rs1012068 polymorphism did not significantly increase HCC risk in the total population (allelic model (OR = 1.32, 95% CI = 1.04-1.67, P = 0.02); the recessive model (OR = 1.42, 95% CI = 0.96-2.10, P = 0.08); the dominant model (OR = 1.43, 95% CI = 1.09-1.87, P = 0.01); the homozygous model (OR = 1.61, 95% CI = 1.01-2.57, P = 0.05); the heterozygous model (OR = 1.39, 95% CI = 1.09-1.79, P = 0.009)). Subgroup analyses based on ethnicity and etiology revealed that the rs1012068 polymorphism, under all five genetic models, was associated with increased HCC risk in Asians or in individuals with chronic HBV infection but not in individuals with chronic HCV infection. A significant association was also observed between rs5998152 and HCV-related HCC risk in Asians chronically infected with HCV under allelic, dominant, and heterozygous models. Conclusion Our study suggests that the DEPDC5 rs1012068 polymorphism increases HCC risk, especially in Asians with chronic HBV infection, while the rs5998152 polymorphism increases HCC risk in Asians with chronic HCV infection.
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Liu S, Miao M, Kang L. Upregulation of MAD2L1 mediated by ncRNA axis is associated with poor prognosis and tumor immune infiltration in hepatocellular carcinoma: A review. Medicine (Baltimore) 2023; 102:e32625. [PMID: 36637946 PMCID: PMC9839239 DOI: 10.1097/md.0000000000032625] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/20/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND The mortality rate and prognosis of patients with hepatocellular carcinoma (HCC) are well known. A variety of highly malignant human cancers express mitotic arrest deficient 2 like 1 (MAD2L1), a transcription factor that plays a critical role in their development and progression. However, MAD2L1's particular mechanisms and effects on HCC remain uncertain. METHODS We performed a pan-cancer analysis for MAD2L1 prognosis and expression using The Cancer Genome Atlas and Genotype-Tissue Expression data in the present study. MAD2L1 may act as an oncogene in HCC, and a combination of in silico analyses, including expression, survival, and correlation analyses, were performed to identify non-coding ribonucleic acids (ncRNAs) that contribute to MAD2L1 overexpression. RESULTS In conclusion, MAD2L1 is most likely regulated by HCP5/miRNA-139-5p/MAD2L1 in HCC based on its upstream ncRNA-related pathway. A significant positive association was also found between MAD2L1 levels and tumor immune cell infiltration, immune cell biomarkers, and immune checkpoint expression. CONCLUSION Our findings demonstrate that ncRNA-mediated upregulation of MAD2L1 in HCC is closely related to poor prognosis and tumor infiltration.
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Affiliation(s)
- Sizhe Liu
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Mingsan Miao
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
| | - Le Kang
- School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou, China
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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Wang H, Jiang Z. Identification and Verification of an Alternative Polyadenylation-Related lncRNA Prognostic Signature for Glioma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2164229. [PMID: 39279987 PMCID: PMC11401696 DOI: 10.1155/2022/2164229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/08/2022] [Accepted: 08/22/2022] [Indexed: 09/18/2024]
Abstract
Due to the high mortality and modality of glioma, it was urgently needed to develop a glioma prognostic assessment system. Previous studies demonstrated that alternative polyadenylation- (APA-) related genes are important in immune response and oncogenesis. mRNA and lncRNA expression information of glioma samples were acquired from CGGA and TCGA databases, and lncRNAs associated with APA were selected through correlation analysis. The prognosis model of APA-related lncRNAs was built by the univariate Cox, random forest, and univariate Cox regression analyses. Glioma samples were assigned into high- and low-risk groups. Independence and effectiveness of the prognostic model were evaluated by Kaplan-Meier analysis, ROC curve, and Cox regression analyses. GO, KEGG enrichment, and GSEA analyses showed that the mainly involved signaling pathways were enriched in cellular immunity and immune signal transduction. We further analyzed expression differences of negative immune regulatory genes and immune cell infiltration degree between two groups. Immune checkpoints CTLA4 and LAG3 and immune suppressors TGFB, IL10, NOS3, and IDO1 and immune cell infiltration were notably upregulated in the high-risk group. The PD1/PDL1 expression was significantly correlated with risk score, showing that the prognostic model of APA-related lncRNA could effectively assess the tumor immune suppression. In conclusion, we established a risk assessment model of APA-related lncRNA in glioma, which could effectively evaluate prognosis of patients with glioma and tumor immune suppression and could provide guidance for clinical treatment.
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Affiliation(s)
- Hui Wang
- Department of Pathology, The First People's Hospital of Fuyang, Hangzhou City, Zhejiang Province 31400, China
| | - ZhiJun Jiang
- Department of Pathology, The First People's Hospital of Fuyang, Hangzhou City, Zhejiang Province 31400, China
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Li J, Tao Y, Cong H, Zhu E, Cai T. Predicting liver cancers using skewed epidemiological data. Artif Intell Med 2022; 124:102234. [DOI: 10.1016/j.artmed.2021.102234] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 11/26/2021] [Accepted: 12/21/2021] [Indexed: 01/04/2023]
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Liu Y, Jing XB, Wang ZC, Han QK. HCP5, as the sponge of miR-1291, facilitates AML cell proliferation and restrains apoptosis via increasing PIK3R5 expression. Hum Genomics 2021; 15:38. [PMID: 34187569 PMCID: PMC8244151 DOI: 10.1186/s40246-021-00340-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 06/15/2021] [Indexed: 11/21/2022] Open
Abstract
Background Acute myeloid leukemia (AML) is recognized as a hematological neoplasm with heterogenetic cytology and short-term outcome. HCP5 has been proven to be related with the pathogenesis of AML. However, the underlying mechanism of HCP5 in AML remains unclear. Methods Clinical profiles of AML patients were downloaded from TCGA and GTEx databases. LncBase and TargetScan online tools were utilized to predict potential targets, and dual-luciferase reporter assay was performed to verify the association between miR-1291 and HCP5 or PIK3R5. Cell Counting Kit 8 and flow cytometry tests were implemented to evaluate the effects of HCP5/miR-1291/PIK3R5 axis in AML cells. Quantitative RT-PCR and Western blot were conducted to detect the expression levels of genes. Results HCP5 and PIK3R5 were significantly increased in AML tissue samples compared with healthy controls. HCP5 facilitated AML cells viability and inhibited apoptosis. There was a positive relationship between HCP5 and PIK3R5, but miR-1291 negatively regulated PIK3R5. Overexpression of PIK3R5 enhanced the promoting effect of HCP5 in the development of AML, while weakened the suppression of miR-1291 to AML progression. Conclusion Our findings manifested that HCP5 was remarkably upregulated in AML and upregulated HCP5 promoted the malignant behaviors of AML cells by mediating miR-1291/PIK3R5 axis, which would provide a new insight for the treatment of AML. Supplementary Information The online version contains supplementary material available at 10.1186/s40246-021-00340-5.
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Affiliation(s)
- Yan Liu
- Department of Hematology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, People's Republic of China
| | - Xue-Bing Jing
- Department of Nursing, Zibo Central Hospital, Zibo, 255000, Shandong, People's Republic of China
| | - Zhen-Cheng Wang
- Department of Hematology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, People's Republic of China
| | - Qing-Kun Han
- Department of Hematology, Zibo Central Hospital, No. 54 Gongqingtuan West Road, Zhangdian District, Zibo, 255000, Shandong, People's Republic of China.
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Zhou Y, Li K, Dai T, Wang H, Hua Z, Bian W, Wang H, Chen F, Ai X. Long non-coding RNA HCP5 functions as a sponge of miR-29b-3p and promotes cell growth and metastasis in hepatocellular carcinoma through upregulating DNMT3A. Aging (Albany NY) 2021; 13:16267-16286. [PMID: 34148029 PMCID: PMC8266334 DOI: 10.18632/aging.203155] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/21/2021] [Indexed: 12/30/2022]
Abstract
Multiple studies have revealed that long non-coding RNA (lncRNAs) served as regulatory factors in modulating tumorigenesis of hepatocellular carcinoma (HCC). In the present study, we demonstrated that lncRNA HCP5 was overexpressed in HCC tissues and cell lines, and these findings were obvious even in metastatic and recurrent cases. Knockdown of HCP5 significantly alleviated cell growth, metastasis, and invasion both in vitro and in vivo through promoting apoptosis and by inactivating the epithelial-mesenchymal transition (EMT) progress. Moreover, miR-29b-3p has been identified as a negatively regulatory target gene of HCP5, and served as a tumor suppressor of HCC to prevent cell proliferation, migration, and invasion. Subsequently, DNMT3A was identified as a downstream regulatory factor of miR-29b-3p, and acted as a participated element of HCC progression by activating AKT phosphorylation. Taken together, our study elucidated for the first time that HCP5 plays a crucial role in HCC via the HCP5/miR-29b-3p/DNMT3A/AKT axis and our findings demonstrated a novel diagnostic and therapeutic strategy with potentiality to treat HCC.
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Affiliation(s)
- Yongping Zhou
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Kuan Li
- Department of Hepatobiliary Surgery, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, Jiangsu, China
| | - Tu Dai
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Hong Wang
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Zhiyuan Hua
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Wuyang Bian
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Hao Wang
- Department of Hepatobiliary Surgery, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Fangming Chen
- Department of Imaging, Wuxi Second Hospital, Nanjing Medical University, Wuxi, Jiangsu, China
| | - Xiaoming Ai
- Department of General Surgery, BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Wang C, Yu G, Xu Y, Liu C, Sun Q, Li W, Sun J, Jiang Y, Ye L. Knockdown of Long Non-Coding RNA HCP5 Increases Radiosensitivity Through Cellular Senescence by Regulating microRNA-128 in Gliomas. Cancer Manag Res 2021; 13:3723-3737. [PMID: 33994812 PMCID: PMC8113609 DOI: 10.2147/cmar.s301333] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/16/2021] [Indexed: 12/17/2022] Open
Abstract
Introduction Glioma is the most common malignant brain tumor in adults. Radiation is a key therapy in glioma. However, the radioresistance of glioma was a big challenge. HLA complex P5 (HCP5) has been reported dysregulated in several types of malignant tumor, including glioma. The role of HCP5 in the radiosensitivity of glioma is so far unknown. The present study aimed to investigate the effect of HCP5 on radiosensitivity in gliomas. Methods The levels of HCP5 and microRNA (miR)-128 were detected using qRT-PCR. The cell growth curve was used to show the cell proliferation and evaluate the radiosensitivity of glioma cells following exposure to X-ray. Senescence-associated β-galactosidase (SA-β-Gal) staining was used to test the cellular senescence. Luciferase reporter and RNA immunoprecipitation (RIP) assays were performed to determine the correlation between HCP5 and miR-128. Results HCP5 level of glioma cells was significantly higher than human astrocytes, whereas miR-128 level was lower in glioma cells. Besides, the HCP5 expression was increased in glioma tissues compared to normal brain tissues (NBTs). Knockdown of HCP5 inhibited cell proliferation and increased radiosensitivity in glioma cells. MiR-128 was predicted to be a target of HCP5. It was demonstrated that HCP5 directly bound to miR-128 and regulated its expression in glioma cells. Furthermore, the effects of HCP5 knockdown on radiosensitivity of glioma cells were attenuated by the inhibitor of miR-128. Conclusion These findings suggested that interaction between lncRNA HCP5 and microRNA-128 could regulate the radiosensitivity of glioma cells by intervening in cellular senescence. This might be used as the potential radio-sensitization targets for glioma therapy.
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Affiliation(s)
- Cuihong Wang
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Guanying Yu
- Department of Gastrointestinal Surgery, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong, 250013, People's Republic of China
| | - Ying Xu
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Chengfei Liu
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Qian Sun
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Wenqing Li
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Junhua Sun
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Yuhua Jiang
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
| | - Lan Ye
- Cancer Center, The Second Hospital of Shandong University, Jinan, Shandong, 250033, People's Republic of China
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Liu WY, Eslam M, Zheng KI, Ma HL, Rios RS, Lv MZ, Li G, Tang LJ, Zhu PW, Wang XD, Byrne CD, Targher G, George J, Zheng MH. Associations of Hydroxysteroid 17-beta Dehydrogenase 13 Variants with Liver Histology in Chinese Patients with Metabolic-associated Fatty Liver Disease. J Clin Transl Hepatol 2021; 9:194-202. [PMID: 34007801 PMCID: PMC8111109 DOI: 10.14218/jcth.2020.00151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Revised: 01/24/2021] [Accepted: 02/07/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIMS In Europeans, variants in the hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) gene impact liver histology in metabolic-associated fatty liver disease (MAFLD). The impact of these variants in ethnic Chinese is unknown. The aim of this study was to investigate the potential associations in Chinese patients. METHODS In total, 427 Han Chinese with biopsy-confirmed MAFLD were enrolled. Two single nucleotide polymorphisms in HSD17B13 were genotyped: rs72613567 and rs6531975. Logistic regression was used to test the association between the single nucleotide polymorphisms and liver histology. RESULTS In our cohort, the minor allele TA of the rs72613567 variant was related to an increased risk of fibrosis [odds ratio (OR): 2.93 (1.20-7.17), p=0.019 for the additive model; OR: 3.32 (1.39-7.91), p=0.007 for the recessive model], representing an inverse association as compared to the results from European cohorts. In contrast, we observed a protective effect on fibrosis for the minor A allele carriers of the HSD17B13 rs6531975 variant [OR: 0.48 (0.24-0.98), p=0.043 for the additive model; OR: 0.62 (0.40-0.94), p=0.025 for the dominant model]. HSD17B13 variants were only associated with fibrosis but no other histological features. Furthermore, HSD17B13 rs6531975 modulated the effect of PNPLA3 rs738409 on hepatic steatosis. CONCLUSIONS HSD17B13 rs72613567 is a risk variant for fibrosis in a Han Chinese MAFLD population but with a different direction for allelic association to that seen in Europeans. These data exemplify the need for studying diverse populations in genetic studies in order to fine map genome-wide association studies signals.
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Affiliation(s)
- Wen-Yue Liu
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Kenneth I. Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Hong-Lei Ma
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Rafael S. Rios
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Min-Zhi Lv
- Department of Biostatistics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gang Li
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Liang-Jie Tang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Pei-Wu Zhu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xiao-Dong Wang
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Christopher D. Byrne
- Southampton National Institute for Health Research Biomedical Research Centre, University Hospital Southampton, Southampton General Hospital, Southampton, UK
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, Sydney, Australia
| | - Ming-Hua Zheng
- NAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Institute of Hepatology, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
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Tu Y, Cai Q, Zhu X, Xu M. Down-regulation of HCP5 inhibits cell proliferation, migration, and invasion through regulating EPHA7 by competitively binding miR-101 in osteosarcoma. ACTA ACUST UNITED AC 2021; 54:e9161. [PMID: 33439936 PMCID: PMC7798137 DOI: 10.1590/1414-431x20209161] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 09/11/2020] [Indexed: 12/19/2022]
Abstract
Patients with osteosarcoma (OS) usually have poor overall survival because of frequent metastasis. Long non-coding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and metastasis. In this study, we investigated the expression and roles of lncRNA human histocompatibility leukocyte antigen (HLA) complex P5 (HCP5) in OS, aiming to provide a novel molecular mechanism for OS. HCP5 was up-regulated both in OS tissues and cell lines and high expression of HCP5 was associated to low survival in OS patients. Down-regulation of HCP5 inhibited cell proliferation, migration, and invasion, suggesting its carcinogenic role in OS. miR-101 was targeted by HCP5 and its expression was decreased in OS. The inhibitor of miR-101 reversed the impact of HCP5 down-regulation on cell proliferation, apoptosis, and metastasis in OS. Ephrin receptor 7 (EPHA7) was proved to be a target of miR-101 and had ability to recover the effects of miR-101 inhibitor in OS. In conclusion, lncRNA HCP5 knockdown suppressed cell proliferation, migration, and invasion, and induced apoptosis through depleting the expression of EPHA7 by binding to miR-101, providing a potential therapeutic strategy of HCP5 in OS.
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Affiliation(s)
- Yangmao Tu
- Department of Orthopedics, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou, China
| | - Qing Cai
- Department of Orthopedics, Jingzhou Hospital of Traditional Chinese Medicine, Jingzhou, China
| | - Xuemei Zhu
- Jingzhou Hospital of Traditional Chinese Medicine - Functional Section, Jingzhou, China
| | - Min Xu
- Jingzhou Institute of Technology, College of Textile and Apparel Design and Art, Jingzhou, China
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13
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Wang R, Cai J, Xie S, Zhao C, Wang Y, Cao D, Li G. T Cell Factor 4 Is Involved in Papillary Thyroid Carcinoma via Regulating Long Non-Coding RNA HCP5. Technol Cancer Res Treat 2020; 19:1533033820983290. [PMID: 33371788 PMCID: PMC7780308 DOI: 10.1177/1533033820983290] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The annual incidence of papillary thyroid carcinoma has increased dramatically. T cell factor 4 (TCF4) is an important component of Wnt signaling pathway.However, the role of TCF4 in PTC remains unknown. In this study, TCF4 was observed to overexpress in PTC patients and cells by qRT-PCR assay. The colony formation assay, Edu staining and transwell assay indicated thatoverexpression of TCF4 promoted cell proliferation and invasion of TCP-1 cells, whereas knockdown of TCF4 inhibited cell proliferation and invasion of IHH-4 cells. To investigate the mechanism of TCF4 in PTC cells, the luciferase assay demonstrated that TCF4 could modulate HCP5 expression. Besides, GLuc-ON promoter reporter assayproved that TCF4 could bind to HCP5 promoter. Further, knockdown of HCP5 could significantly up-regulated miR-15a, miR-216a-5p, miR-22-3p, miR-139-5p, miR-203, miR-27a-3p and miR-320, and down-regulated miR-186-5p in IHH-4 cells, which might be potential downstream of TFC4/HCP5 axis. In conclusion, up-regulation TCF4 can promote HCP5 expression via binding to HCP5 promoter. It may be the first time to prove that TCF4 regulates HCP5 in PTC, which provides a novel sight for treatment of PTC.
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Affiliation(s)
- Rui Wang
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Jidong Cai
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Shangnao Xie
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Chunlei Zhao
- Department of Nuclear Medicine, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Yi Wang
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Deming Cao
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
| | - Gang Li
- Surgical Oncology, Hangzhou Cancer Hospital, Hangzhou City, Zhejiang Province, China
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14
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Ning L, Ko JMY, Yu VZ, Ng HY, Chan CKC, Tao L, Lam SY, Leong MML, Ngan RKC, Kwong DLW, Lee AWM, Ng WT, Cheng A, Tung S, Lee VHF, Lam KO, Kwan CK, Li WS, Yau S, Bei JX, Lung ML. Nasopharyngeal carcinoma MHC region deep sequencing identifies HLA and novel non-HLA TRIM31 and TRIM39 loci. Commun Biol 2020; 3:759. [PMID: 33311639 PMCID: PMC7733486 DOI: 10.1038/s42003-020-01487-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/14/2020] [Indexed: 12/13/2022] Open
Abstract
Despite pronounced associations of major histocompatibility complex (MHC) regions with nasopharyngeal carcinoma (NPC), causal variants underlying NPC pathogenesis remain elusive. Our large-scale comprehensive MHC region deep sequencing study of 5689 Hong Kong Chinese identifies eight independent NPC-associated signals and provides mechanistic insight for disrupted transcription factor binding, altering target gene transcription. Two novel protective variants, rs2517664 (Trs2517664 = 4.6%, P = 6.38 × 10−21) and rs117495548 (Grs117495548 = 3.0%, P = 4.53 × 10−13), map near TRIM31 and TRIM39/TRIM39-RPP21; multiple independent protective signals map near HLA-B including a previously unreported variant, rs2523589 (P = 1.77 × 10−36). The rare HLA-B*07:05 allele (OR < 0.015, P = 5.83 × 10−21) is absent in NPC, but present in controls. The most prevalent haplotype lacks seven independent protective alleles (OR = 1.56) and the one with additional Asian-specific susceptibility rs9391681 allele (OR = 2.66) significantly increased NPC risk. Importantly, this study provides new evidence implicating two non-human leukocyte antigen (HLA) genes, E3 ubiquitin ligases, TRIM31 and TRIM39, impacting innate immune responses, with NPC risk reduction, independent of classical HLA class I/II alleles. Here the authors report a major histocompatibility complex (MHC) association analysis for nasopharyngeal carcinoma in Chinese individuals from Hong Kong, finding 8 independent associated loci associated with lower risk for developing nasopharyngeal carcinoma. Two non-human leukocyte antigen (HLA) genes are E3 ubiquitin ligases, TRIM31 and TRIM39, having a role in the innate immune response and implicating the importance of host Epstein-Barr virus interactions in this cancer.
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Affiliation(s)
- Lvwen Ning
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Josephine Mun-Yee Ko
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.
| | - Valen Zhuoyou Yu
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Hoi Yan Ng
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Candy King-Chi Chan
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Lihua Tao
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Shiu-Yeung Lam
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Merrin Man-Long Leong
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Roger Kai-Cheong Ngan
- Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Dora Lai-Wan Kwong
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Anne Wing-Mui Lee
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Wai-Tong Ng
- Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Department of Clinical Oncology, Pamela Youde Nethersole Eastern Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Ashley Cheng
- Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Department of Oncology, Princess Margaret Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Stewart Tung
- Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Victor Ho-Fun Lee
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Ka-On Lam
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.,Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China
| | - Chung-Kong Kwan
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Wing-Sum Li
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Stephen Yau
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong (Special Administrative Region), People's Republic of China
| | - Jin-Xin Bei
- Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, 510060, Guangzhou, People's Republic of China
| | - Maria Li Lung
- Department of Clinical Oncology, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China. .,Center for Nasopharyngeal Carcinoma Research, University of Hong Kong, Hong Kong (Special Administrative Region), People's Republic of China.
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15
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Moaz IM, Abdallah AR, Yousef MF, Ezzat S. Main insights of genome wide association studies into HCV-related HCC. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-019-0013-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Abstract
Background
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-mortality globally. Hepatocarcinogenesis is a complex multifactorial process. Host genetic background appeared to play a crucial role in the progression of HCC among chronic hepatitis C patients, especially in the era of Genome Wide Association Studies (GWAS) which allowed us to study the association of millions of single nucleotide polymorphisms (SNPs) with different complex diseases. This article aimed to review the discovered SNPs associated with the risk of HCV-related HCC development which was reported in the published GWA studies and subsequent validation studies and also try to explain the possible functional pathways.
Main text
We reviewed the recent GWA studies which reported several new loci associated with the risk of HCV-related HCC, such as (SNPs) in MHC class I polypeptide-related sequence A (MICA), DEP domain-containing 5 (DEPDC5), Tolloid-like protein 1 (TLL1), and human leukocyte antigen (HLA) genes. We also explained the possible underlying biological mechanisms that affect the host immune response pathways. Additionally, we discussed the controversial results reported by the subsequent validation studies of different ethnicities.
Conclusions
Although GWA studies reported strong evidence of the association between the identified SNPs and the risk of HCV-related HCC development, more functional experiments are necessary to confirm the defined roles of these genetic mutations for the future clinical application in different populations.
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16
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Kubota N, Fujiwara N, Hoshida Y. Clinical and Molecular Prediction of Hepatocellular Carcinoma Risk. J Clin Med 2020; 9:jcm9123843. [PMID: 33256232 PMCID: PMC7761278 DOI: 10.3390/jcm9123843] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Prediction of hepatocellular carcinoma (HCC) risk becomes increasingly important with recently emerging HCC-predisposing conditions, namely non-alcoholic fatty liver disease and cured hepatitis C virus infection. These etiologies are accompanied with a relatively low HCC incidence rate (~1% per year or less), while affecting a large patient population. Hepatitis B virus infection remains a major HCC risk factor, but a majority of the patients are now on antiviral therapy, which substantially lowers, but does not eliminate, HCC risk. Thus, it is critically important to identify a small subset of patients who have elevated likelihood of developing HCC, to optimize the allocation of limited HCC screening resources to those who need it most and enable cost-effective early HCC diagnosis to prolong patient survival. To date, numerous clinical-variable-based HCC risk scores have been developed for specific clinical contexts defined by liver disease etiology, severity, and other factors. In parallel, various molecular features have been reported as potential HCC risk biomarkers, utilizing both tissue and body-fluid specimens. Deep-learning-based risk modeling is an emerging strategy. Although none of them has been widely incorporated in clinical care of liver disease patients yet, some have been undergoing the process of validation and clinical development. In this review, these risk scores and biomarker candidates are overviewed, and strategic issues in their validation and clinical translation are discussed.
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17
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Zou Y, Chen B. Long non-coding RNA HCP5 in cancer. Clin Chim Acta 2020; 512:33-39. [PMID: 33245911 DOI: 10.1016/j.cca.2020.11.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 11/09/2020] [Accepted: 11/11/2020] [Indexed: 12/13/2022]
Abstract
Cancer remains a major threat to human health worldwide. Long non-coding RNA (lncRNA) comprises a group of single-stranded RNA with lengths longer than 200 bp. LncRNAs are aberrantly expressed and play a variety of roles involving multiple cellular processes in cancer. Histocompatibility leukocyte antigen complex P5 (HCP5), initially reported in 1993, is an important lncRNA located between the MICA and MICB genes in MHC I region. HCP5 is involved many autoimmune diseases as well as malignancies. Abnormal HCP5 expression occurs in many types of cancer and its dysregulation appears closely associated with tumor progression. HCP5 is also involved in anti-tumor drug resistance as well. As such, HCP5 represents a promising biomarker and therapeutic target in cancer. In this review, we summarize recent researches and provide an overview of the role and mechanism of HCP5 in human cancer.
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Affiliation(s)
- Yuanzhang Zou
- Department of Urology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Binghai Chen
- Department of Urology, Affiliated Hospital of Jiangsu University, Jiangsu University, Zhenjiang, Jiangsu, China.
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18
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Singh G, Yoshida EM, Rathi S, Marquez V, Kim P, Erb SR, Salh BS. Biomarkers for hepatocellular cancer. World J Hepatol 2020; 12:558-573. [PMID: 33033565 PMCID: PMC7522562 DOI: 10.4254/wjh.v12.i9.558] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. If diagnosed early, curative treatment options such as surgical resection, loco-regional therapies, and liver transplantation are available to patients, increasing their chances of survival and improving their quality of life. Unfortunately, most patients are diagnosed with late stage HCC where only palliative treatment is available. Therefore, biomarkers which could detect HCC early with a high degree of sensitivity and specificity, may play a crucial role in the diagnosis and management of the disease. This review will aim to provide an overview of the different biomarkers of HCC comprising those used in the diagnosis of HCC in at risk populations, as well as others with potential for prognosis, risk predisposition and prediction of response to therapeutic intervention.
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Affiliation(s)
- Gurjot Singh
- Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Eric M Yoshida
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Sahaj Rathi
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Vladimir Marquez
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Peter Kim
- Division of Oncological Surgery, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Siegfried R Erb
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
| | - Baljinder S Salh
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver V5Z 1M9, Canada
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19
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Fujiwara N, Qian T, Koneru B, Hoshida Y. Omics-derived hepatocellular carcinoma risk biomarkers for precision care of chronic liver diseases. Hepatol Res 2020; 50:817-830. [PMID: 32323426 PMCID: PMC8318383 DOI: 10.1111/hepr.13506] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/13/2020] [Accepted: 04/18/2020] [Indexed: 02/07/2023]
Abstract
Precise hepatocellular carcinoma (HCC) risk prediction will play increasingly important roles with the contemporary HCC etiologies, that is, non-alcoholic fatty liver disease and resolved hepatitis C virus infection. Because the HCC incidence rate in this emerging patient population is relatively low (~1% per year), identification of a subset of patients at the highest risk is critical to concentrate the effort and resources of regular HCC screening to those who most need it. Omics profiling has been derived using several candidate HCC risk biomarkers, which could refine HCC screening by enabling individual risk-based personalized or risk-stratified patient management. Various types of biomolecules have been explored as sources of information to predict HCC risk at various time horizons. Germline DNA polymorphisms likely reflect race/ethnicity- and/or etiology-specific susceptibility to HCC development or chronic liver disease progression toward carcinogenesis. Transcriptomic dysregulations in the diseased liver capture functional molecular status supporting oncogenesis such as inflammatory pathway and myofibroblast activation. Circulating nucleic acids, proteins, and metabolites could serve as less-invasive measures of molecular HCC risk. Characterization of gut microbiota could also inform HCC risk estimation. Each biomarker could have its niche of clinical application depending on logistics of use, performance, and costs with a goal to eventually improve patient prognosis as a part of the whole algorithm of chronic liver disease management.
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Affiliation(s)
- Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tongqi Qian
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Bhuvaneswari Koneru
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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20
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Frías M, Rivero-Juárez A, Machuca I, Camacho Á, Rivero A. The outlook for precision medicine for the treatment of chronic hepatitis C infection: challenges and opportunities. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2020. [DOI: 10.1080/23808993.2020.1764346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Mario Frías
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero-Juárez
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Isabel Machuca
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Ángela Camacho
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
| | - Antonio Rivero
- Clinical Virology and Zoonoses, Hospital Universitario Reina Sofía de Córdoba. Instituto Maimonides de Investigación Biomédica de Córdoba (IMIBIC), Universidad de Córdoba, Spain
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21
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Association between MICA rs2596542 Polymorphism with the Risk of Hepatocellular Carcinoma in Chronic Hepatitis C Patients. Pathol Oncol Res 2019; 26:1519-1525. [PMID: 31471884 DOI: 10.1007/s12253-019-00738-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 08/27/2019] [Indexed: 12/30/2022]
Abstract
In this study we investigated the impact of rs2596542A/G single nucleotide polymorphism (SNP) in the major histocompatibility complex class I chain-related sequence A (MICA) gene on HCV-induced hepatocellular carcinoma (HCC) susceptibility in a Brazilian population. In total, 252 HCV-infected patients (98 with HCV-induced HCC and 154 non-malignant HCV-induced liver cirrhosis) were enrolled and 98 healthy control subjects (negative anti-HCV). The MICA rs2596542 SNP genotypes were determined by real-time PCR assay. No differences in MICA genotype frequencies between HCV-induced cirrhosis patients and controls were observed. However, genotype frequencies of rs2596542A/G SNP were statistically different between HCV-induced HCC patients and controls (p = 0.048), and also between HCC and HCV-induced cirrhosis patients (p = 0.039). The highest frequency of the rs2596542AA genotype was observed in HCC patients (31.6%) when compared with HCV-induced cirrhosis patients (18.8%) and healthy controls (19.4%). Also, rs2596542AA genotype carriers have an increased risk for HCC when compared to HCV-induced cirrhosis status [odds ratio (OR) = 1.99; 95% confidence interval (CI) = 1.06-3.74, p = 0.020)] and healthy individuals (OR = 1.92, 95% CI = 1.00-3.70, p = 0.049). Taken together our study suggest that MICA rs2596542 SNP impacts HCV-induced HCC susceptibility suggesting that genetic variants in MICA are of clinical relevance to hepatocarcinogenesis by impacting host immune response in chronic HCV infection.
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22
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Luo X, Wang Y, Shen A, Deng H, Ye M. Relationship between the rs2596542 polymorphism in the MICA gene promoter and HBV/HCV infection-induced hepatocellular carcinoma: a meta-analysis. BMC MEDICAL GENETICS 2019; 20:142. [PMID: 31419949 PMCID: PMC6697945 DOI: 10.1186/s12881-019-0871-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/16/2019] [Accepted: 08/02/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Various studies have investigated the relationship between the polymorphism, rs2596542, in the promoter of the major histocompatibility complex class I-related gene A (MICA) gene with susceptibility to hepatitis B virus (HBV)/ hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC); however, the results are inconclusive. This meta-analysis was conducted to investigate the relationship between rs2596542 and HCV/HBV-induced HCC. METHODS Three electronic scientific publication databases (MEDLINE, Web of Science, and Embase) were screened using specific search terms and relevant literature identified using literature traceability methods. Selected publications were evaluated according to the inclusion and exclusion criteria, and 11 articles were included in the study. Effect size information (odds ratio [OR] and corresponding 95% confidence interval [CI]) were obtained following quality assessment and data extraction from the included publications, and a meta-analysis conducted. RESULTS A total of 11 publications were included in the study, including 4582 patients with HCC and 21,095 non-HCC patients. TT genotype at rs2596542 was a risk factor for the development of HCC in patients with HCV/HBV infection (OR = 1.248, 95% CI: 1.040-1.499, P = 0.017), particularly those with HCV infection (OR = 1.326, 95% CI: 1.101-1.599, P = 0.003) and Asians (OR = 1.273, 95% CI: 1.002-1.618, P = 0.048), or when the control group was patients with chronic hepatitis C (CHC) (OR = 1.506, 95% CI: 1.172-1.936, P = 0.001). CONCLUSION The findings of this meta-analysis suggest that the rs2596542 variant in the MICA promoter region may affect MICA and soluble MICA (sMICA) protein expression, thereby influencing physiological vulnerability to HCC cells and the development of HCC. These data provide a theoretical basis for the diagnosis and treatment of patients with HCC and viral hepatitis infection.
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Affiliation(s)
- Xiaojun Luo
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Yu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Ai Shen
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Hejun Deng
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, China
| | - Min Ye
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, No. 181 Hanyu Road, Shapingba District, Chongqing, 400030, China.
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23
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Wang L, Luan T, Zhou S, Lin J, Yang Y, Liu W, Tong X, Jiang W. LncRNA HCP5 promotes triple negative breast cancer progression as a ceRNA to regulate BIRC3 by sponging miR-219a-5p. Cancer Med 2019; 8:4389-4403. [PMID: 31215169 PMCID: PMC6675706 DOI: 10.1002/cam4.2335] [Citation(s) in RCA: 75] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 05/08/2019] [Accepted: 05/26/2019] [Indexed: 12/29/2022] Open
Abstract
Emerging evidence has suggested that long noncoding RNAs (lncRNA) involved in the development and progression of cancer. Triple negative breast cancer (TNBC) was an aggressive type of breast cancer with high rates of cancer recurrence and metastasis. The pathogenesis of TNBC is largely unknown. Recent studies suggested that lncRNA HCP5 plays an important role in carcinogenesis. The purpose of this study was to examine the function and mechanism of HCP5 in TNBC. We observed that HCP5 was upregulated in TNBC cell lines and specimens. HCP5 knockdown induced TNBC cell apoptosis, and inhibited cell proliferation and orthotopic xenograft tumor growth. RNA sequencing and antibody array suggested that HCP5 achieves its functions through regulating apoptosis pathway. Bioinformatics, luciferase and RIP experiments proved that both HCP5 and BIRC3 could competitively bind to miR‐219a‐5p. Increased BIRC3 and decreased miR‐219a‐5p were observed in TNBC tissues and cell lines. We then performed gain‐ and loss‐of‐function studies as well as rescue experiments in TNBC cells. The decrease of proliferation and migration due to HCP5 knockdown could be rescued when miR‐219a‐5p inhibitor or BIRC3 was transfected and vice versa. Our study suggested that lncRNA HCP5 promotes TNBC progression as a ceRNA to regulate BIRC3 by sponging miR‐219a‐5p. In a word, we revealed a new signaling pathway to mediate TNBC, and provided HCP5 as a new target for improving treatment of TNBC.
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Affiliation(s)
- Lihong Wang
- Department of Pathophysiology, Medical College of Southeast University, Nanjing, China
| | - Tian Luan
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Shunheng Zhou
- College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China
| | - Jing Lin
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Yue Yang
- Institute of Cancer Prevention and Treatment, Heilongjiang Academy of Medical Science, Harbin Medical University, Harbin, China
| | - Wei Liu
- Department of Pathology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiao Tong
- Department of Pathophysiology, Medical College of Southeast University, Nanjing, China
| | - Wei Jiang
- College of Automation Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing, China
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Wang H, Cao H, Xu Z, Wang D, Zeng Y. SNP rs2596542G>A in MICA is associated with risk of hepatocellular carcinoma: a meta-analysis. Biosci Rep 2019; 39:BSR20181400. [PMID: 30967497 PMCID: PMC6504665 DOI: 10.1042/bsr20181400] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 04/06/2019] [Accepted: 04/07/2019] [Indexed: 02/05/2023] Open
Abstract
The association of major histocompatibility complex class I chain-related gene A (MICA) single nucleotide polymorphism (SNP) rs2596542G>A and hepatocellular carcinoma (HCC) has been broadly studied, with inconsistent results. Therefore, we conducted the current meta-analysis to better elucidate the roles of SNP rs2596542G>A in HCC. Eligible articles were searched in PubMed, CNKI, Wanfang, Embase, VIP, Web of Science, and CBM databases up to November 2018. Odds ratios (ORs) and 95% CIs were applied. A total of 11 articles, including 4528 HCC patients and 16,625 control subjects, were analyzed. Results revealed that rs2596542G>A was significantly associated with HCC in the heterozygote (G/A versus A/A, P=0.006, OR = 0.854; 95% CI: 0.763-0.956); and dominant (G/G + G/A versus A/A; P=0.021; OR = 0.796; 95% CI: 0.655-0.967) genetic models. Nevertheless, we also detected significant associations between rs2596542G>A and HCV-induced HCC. Additionally, according to our analyses, SNP rs2596542G>A was not correlated with HBV-induced HCC. In conclusion, our findings suggest that MICA SNP rs2596542G>A is associated with HCC susceptibility amongst the Asian, Caucasian, and African ethnicity in certain genetic models. Specifically, MICA SNP rs2396542G>A is associated with risk of HCV-induced HCC, not HBV-induced HCC.
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Affiliation(s)
- Haichuan Wang
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
| | - Hui Cao
- Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Zhong Xu
- Department of Gastroenterology, Guizhou Provincial People's Hospital, Guiyang, China
| | - Dong Wang
- Department of Surgery, Transplant and Stem Cell Immunobiology (TSI-) Lab, University of California, San Francisco (UCSF), San Francisco, CA, U.S.A
| | - Yong Zeng
- Department of Liver Surgery, Liver Transplantation Division, West China Hospital, Sichuan University, Chengdu, China
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Chen J, Zhao D, Meng Q. Knockdown of HCP5 exerts tumor-suppressive functions by up-regulating tumor suppressor miR-128-3p in anaplastic thyroid cancer. Biomed Pharmacother 2019; 116:108966. [PMID: 31102936 DOI: 10.1016/j.biopha.2019.108966] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 05/08/2019] [Accepted: 05/08/2019] [Indexed: 02/07/2023] Open
Abstract
Anaplastic thyroid cancer (ATC) is a rare type of thyroid cancer with a high mortality rate. HLA complex P5 (HCP5), a long non-coding RNA (lncRNA), has been shown to be implicated in several types of cancer, such as follicular thyroid carcinoma (PTC), the main type of thyroid cancer. However, the role of HCP5 in ATC remains unclear. The present study aimed to investigate the expression of HCP5 in ATC and its potential roles. The expression levels of HCP5 and microRNA (miR)-128-3p were tested using qRT-PCR. MTT assay was performed to detect cell viability. Cell apoptosis was evaluated by detecting apoptotic rate and caspase-3/7 activity. Luciferase reporter and RNA immunoprecipitation (RIP) assays were carried out to confirm the association between HCP5 and miR-128-3p. Compared with human thyroid follicular cell line Nthy-ori 3-1 cells, HCP5 expression level was significantly increased in ATC cell lines. Besides, HCP5 expression level was increased in ATC tissues when compared with adjacent normal tissues. Knockdown of HCP5 reduced cell viability, while elevated apoptotic rate and caspase-3/7 activity in ARO and SW1736 cells. MiR-128-3p was predicted to be a target gene of HCP5. The expression level of miR-128-3p was significantly decreased in ATC cells and tissues, as compared to Nthy-ori 3-1 cells and adjacent normal tissues, respectively. MiR-128-3p overexpression reduced ATC cell viability, and induced cell apoptosis. HCP5 directly bound to miR-128-3p and regulated the expression of miR-128-3p in ARO and SW1736 cells. Furthermore, the effects of HCP5 knockdown on ATC cell viability and apoptosis were attenuated by the inhibitor of miR-128-3p. These findings suggested that knockdown of HCP5 exerted anti-tumor effect via sponging miR-128-3p in ATC, which might provide a potential approach for the treatment of ATC.
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Affiliation(s)
- Jing Chen
- Department of Endocrinology, Shanxian Central Hospital, Heze 274300, China
| | - Dongjing Zhao
- Department of Endocrinology, Shanxian Central Hospital, Heze 274300, China
| | - Qiang Meng
- Department of Endocrinology, Affiliated Hospital of Jining Medical University, No. 89 Guhuai Road, Jining 272000, China.
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Abstract
Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline deoxyribonucleic acid polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.
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Jiang L, Wang R, Fang L, Ge X, Chen L, Zhou M, Zhou Y, Xiong W, Hu Y, Tang X, Li G, Li Z. HCP5 is a SMAD3-responsive long non-coding RNA that promotes lung adenocarcinoma metastasis via miR-203/SNAI axis. Am J Cancer Res 2019; 9:2460-2474. [PMID: 31131047 PMCID: PMC6525996 DOI: 10.7150/thno.31097] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 03/23/2019] [Indexed: 12/24/2022] Open
Abstract
Introduction: Transforming growth factor-beta (TGFβ) signaling plays a vital role in lung adenocarcinoma (LUAD) progression. However, the involvement of TGFβ-regulated long non-coding RNAs (lncRNAs) in metastasis of LUAD remains poorly understood. Methods: We performed bioinformatic analyses to identify putative lncRNAs regulated by TGF-β/SMAD3 and validated the results by quantitative PCR in LUAD cells. We performed luciferase reporter and chromatin immunoprecipitation assays to demonstrate the transcriptional regulation of the lncRNA histocompatibility leukocyte antigen complex P5 (HCP5) we decided to focus on. Stable HCP5 knockdown and HCP5-overexpressing A549 cell variants were generated respectively, to study HCP5 function and understand its mechanism of action. We also confirmed our findings in mouse xenografts and metastasis models. We analyzed the correlation between the level of lncRNA expression with EGFR, KRAS mutations, smoke state and prognostic of LUAD patients. Results: We found that the lncRNA HCP5 is induced by TGFβ and transcriptionally regulated by SMAD3, which promotes LUAD tumor growth and metastasis. Moreover, HCP5 is overexpressed in tumor tissues of patients with LUAD, specifically in patients with EGFR and KRAS mutations and current smoker. HCP5 high expression level is positively correlated with poor prognosis of patients with LUAD. Finally, we demonstrated that upregulation of HCP5 increases the expression of Snail and Slug by sponging the microRNA-203 (miR-203) and promoting epithelial-mesenchymal transition (EMT) in LUAD cells. Conclusions: Our work demonstrates that the lncRNA HCP5 is transcriptionally regulated by SMAD3 and acts as a new regulator in the TGFβ/SMAD signaling pathway. Therefore, HCP5 can serve as a potential therapeutic target in LUAD.
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Kuang XJ, Mo DC, Qin Y, Ahir BK, Wang JJ, Peng Z, Deng ZL. Single nucleotide polymorphism of rs2596542 and the risk of hepatocellular carcinoma development: A meta-analysis. Medicine (Baltimore) 2019; 98:e14767. [PMID: 30882647 PMCID: PMC6426553 DOI: 10.1097/md.0000000000014767] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Major histocompatibility complex class I-related chain A (MICA) is considered as a tumor antigen, and its expression is affected by its genetic polymorphisms. However, the relationship between rs2596542 polymorphisms in MICA promoter region and hepatocellular carcinoma (HCC) is not fully elucidated so far. This study aims to explore the relationship between single nucleotide polymorphism of rs2596542 and the risk of HCC development through meta-analysis. METHODS MEDLINE, Web of Science, and EMBASE databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between MICA rs2596542 polymorphism and susceptibility to HCC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS Fourteen case-control studies involving 4,900 HCC cases and 19,519 controls were included. The MICA rs2596542C allele was significantly associated with decreased risk of HCC based on allelic contrast (OR = 0.76, 95% CI = 0.69-0.83, P < .001), homozygote comparison (OR = 0.57, 95% CI = 0.48-0.69, P < .001), and a recessive genetic model (OR = 0.77, 95% CI = 0.65-0.91, P < .001), whereas patients carrying the MICA rs2596542TT genotype had significantly higher risk of HCC than those with the CT or CC genotype (TT vs CT + CC, OR = 1.57, 95% CI = 1.36-1.81, P < .001). Subgroups analyses based on the ethnic or the source of control groups found very similar findings. CONCLUSION The C allele in MICA rs2596542 is a protective factor for hepatocarcinogenesis, whereas the T allele is a risk factor. Further large and well-designed studies are needed to confirm this conclusion.
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Affiliation(s)
- Xue-Jun Kuang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou
| | - Dun-Chang Mo
- Department of Radiotherapy, The Third Affiliated Hospital of Guangxi Medical University, Nanning
| | - Yan Qin
- Department of Surgical Oncology, Affiliated Tumor Hospital of Guangxi University, Nanning
| | - Bhavesh K. Ahir
- Section of Hematology and Oncology, Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Jian-Jun Wang
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou
| | - Zhao Peng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou
| | - Zu-Liang Deng
- Department of Hepatobiliary Surgery, The Affiliated Hospital of Xiangnan University, Chenzhou
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He M, Lin Y, Xu Y. Identification of prognostic biomarkers in colorectal cancer using a long non-coding RNA-mediated competitive endogenous RNA network. Oncol Lett 2019; 17:2687-2694. [PMID: 30854042 PMCID: PMC6365949 DOI: 10.3892/ol.2019.9936] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is a highly malignant gastrointestinal tumor accompanied by poor prognosis. Long non-coding RNA (lncRNA) plays an important role in the progression and physiology of tumors as it competes with endogenous RNAs, including miRNA and mRNA. In the present study, a multi-step computational method was used to build a CRC-related functional lncRNA-mediated competitive endogenous RNA (ceRNA) network (LMCN). lncRNAs with more degrees and betweenness centrality (BC) were screened out as hub lncRNAs. Then functional enrichment analyses of lncRNAs were carried out from the Gene Ontology (GO) and Reactome pathway databases based on the 'guilt by association' principle. As a result, lncRNAs in the LMCN displayed specific topological characteristics in accordance with the regulatory correlation of coding mRNAs in CRC pathology. HCP5, EPB41L4A-AS1, SNHG12, and LINC00649 were screened out as hub lncRNAs which were more significantly related to the development and prognosis of CRC. The hub lncRNAs in CRC were obviously involved in functions of cell cycle arrest, vacuolar transport, histone modification, and in pathways of GPCR, signaling by Rho GTPases, axon guidance pathways, meaning that they might be potential biomarkers for diagnosis, evaluation and gene-targeted therapy of CRC. Thus, the LMCN construction method could accelerate lncRNA discovery and therapeutic development in CRC.
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Affiliation(s)
- Minjie He
- Department of Medical Oncology, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650000, P.R. China
| | - Yan Lin
- Department of Oncology, The Affiliated Traditional Chinese Medical Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830000, P.R. China
| | - Yuzhen Xu
- Department of Gastrointestinal Surgery, Xuzhou Hospital Affiliated to Medical School of Southeast University, Xuzhou, Jiangsu 221009, P.R. China
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O'Brien TR, Yang HI, Groover S, Jeng WJ. Genetic Factors That Affect Spontaneous Clearance of Hepatitis C or B Virus, Response to Treatment, and Disease Progression. Gastroenterology 2019; 156:400-417. [PMID: 30287169 DOI: 10.1053/j.gastro.2018.09.052] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Revised: 09/21/2018] [Accepted: 09/24/2018] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) and hepatitis B virus (HBV) infections can lead to cirrhosis, end-stage liver disease, and hepatocellular carcinoma. Over the past decade, studies of individuals infected with these viruses have established genetic associations with the probability of developing a chronic infection, risk of disease progression, and likelihood of treatment response. We review genetic and genomic methods that have been used to study risk of HBV and HCV infection and patient outcomes. For example, genome-wide association studies have linked a region containing the interferon lambda genes to spontaneous and treatment-induced clearance of HCV. We review the genetic variants associated with HCV and HBV infection, and how these variants affect specific expression or activities of their products. Further studies of these variants could provide insights into risk factors for and mechanisms of chronic infection and disease progression, as well as new strategies for treatment.
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Affiliation(s)
- Thomas R O'Brien
- Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland.
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica, Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Sarah Groover
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, Oklahoma
| | - Wen-Juei Jeng
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Unit, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
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31
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Sasaki R, Kanda T, Kato N, Yokosuka O, Moriyama M. Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response. World J Hepatol 2018; 10:898-906. [PMID: 30631394 PMCID: PMC6323517 DOI: 10.4254/wjh.v10.i12.898] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 11/08/2018] [Accepted: 11/15/2018] [Indexed: 02/06/2023] Open
Abstract
The introduction of a direct-acting antiviral (DAA) for patients with hepatitis C virus (HCV) infection, could lead to higher sustained virologic response (SVR) rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma (HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.
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Affiliation(s)
- Reina Sasaki
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tatsuo Kanda
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Itabashi-ku 173-8610, Japan.
| | - Naoya Kato
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology and Nephrology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Itabashi-ku 173-8610, Japan
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Ehsani R, Drabløs F. Measures of co-expression for improved function prediction of long non-coding RNAs. BMC Bioinformatics 2018; 19:533. [PMID: 30567492 PMCID: PMC6300029 DOI: 10.1186/s12859-018-2546-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 11/28/2018] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Almost 16,000 human long non-coding RNA (lncRNA) genes have been identified in the GENCODE project. However, the function of most of them remains to be discovered. The function of lncRNAs and other novel genes can be predicted by identifying significantly enriched annotation terms in already annotated genes that are co-expressed with the lncRNAs. However, such approaches are sensitive to the methods that are used to estimate the level of co-expression. RESULTS We have tested and compared two well-known statistical metrics (Pearson and Spearman) and two geometrical metrics (Sobolev and Fisher) for identification of the co-expressed genes, using experimental expression data across 19 normal human tissues. We have also used a benchmarking approach based on semantic similarity to evaluate how well these methods are able to predict annotation terms, using a well-annotated set of protein-coding genes. CONCLUSION This work shows that geometrical metrics, in particular in combination with the statistical metrics, will predict annotation terms more efficiently than traditional approaches. Tests on selected lncRNAs confirm that it is possible to predict the function of these genes given a reliable set of expression data. The software used for this investigation is freely available.
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Affiliation(s)
- Rezvan Ehsani
- Department of Mathematics, University of Zabol, Zabol, Iran. .,Department of Bioinformatics, University of Zabol, Zabol, Iran.
| | - Finn Drabløs
- Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, NO-7491, Trondheim, Norway.
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Kubesch A, Quenstedt L, Saleh M, Rüschenbaum S, Schwarzkopf K, Martinez Y, Welsch C, Zeuzem S, Welzel TM, Lange CM. Vitamin D deficiency is associated with hepatic decompensation and inflammation in patients with liver cirrhosis: A prospective cohort study. PLoS One 2018; 13:e0207162. [PMID: 30408125 PMCID: PMC6224127 DOI: 10.1371/journal.pone.0207162] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 10/25/2018] [Indexed: 12/14/2022] Open
Abstract
Background Vitamin D is required to maintain the integrity of the intestinal barrier and inhibits inflammatory signaling pathways. Objective Vitamin D deficiency might be involved in cirrhosis-associated systemic inflammation and risk of hepatic decompensation in patients with liver cirrhosis. Methods Outpatients of the Hepatology Unit of the University Hospital Frankfurt with advanced liver fibrosis and cirrhosis were prospectively enrolled. 25-hydroxyvitamin D (25(OH)D3) serum concentrations were quantified and associated with markers of systemic inflammation / intestinal bacterial translocation and hepatic decompensation. Results A total of 338 patients with advanced liver fibrosis or cirrhosis were included. Of those, 51 patients (15%) were hospitalized due to hepatic decompensation during follow-up. Overall, 72 patients (21%) had severe vitamin D deficiency. However, patients receiving vitamin D supplements had significantly higher 25(OH)D3 serum levels compared to patients without supplements (37 ng/mL vs. 16 ng/ml, P<0.0001). Uni- and multivariate analyses revealed an independent association of severe vitamin D deficiency with the risk of hepatic decompensation during follow-up (multivariate P = 0.012; OR = 3.25, 95% CI = 1.30–8.2), together with MELD score, low hemoglobin concentration, low coffee consumption, and presence of diabetes. Of note, serum levels of C-reactive protein, IL-6 and soluble CD14 were significantly higher in patients with versus without severe vitamin D deficiency, and serum levels of soluble CD14 levels declined in patients with de novo supplementation of vitamin D (median 2.15 vs. 1.87 ng/mL, P = 0.002). Conclusions In this prospective cohort study, baseline vitamin D levels were inversely associated with liver-cirrhosis related systemic inflammation and the risk of hepatic decompensation.
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Affiliation(s)
- Alica Kubesch
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
- * E-mail:
| | - Leonie Quenstedt
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Maged Saleh
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Sabrina Rüschenbaum
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Katharina Schwarzkopf
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Yolanda Martinez
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Tania M. Welzel
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
| | - Christian M. Lange
- Department of Internal Medicine 1, Goethe-University Hospital Frankfurt, Frankfurt, Germany
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Saleh M, Welsch C, Cai C, Döring C, Gouttenoire J, Friedrich J, Haselow K, Sarrazin C, Badenhoop K, Moradpour D, Zeuzem S, Rueschenbaum S, Lange CM. Differential modulation of hepatitis C virus replication and innate immune pathways by synthetic calcitriol-analogs. J Steroid Biochem Mol Biol 2018; 183:142-151. [PMID: 29885880 DOI: 10.1016/j.jsbmb.2018.06.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 05/10/2018] [Accepted: 06/06/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Vitamin D signaling is involved in infectious and non-infectious liver diseases, yet the natural vitamin D metabolites are suboptimal therapeutic agents. In the present study, we therefore aimed to explore the potential and mechanism of selected calcitriol analogs to regulate the hepatocellular transcriptome and to inhibit hepatitis C virus (HCV) in comparison with calcitriol. METHODS Human hepatoma cell lines and primary human macrophages were stimulated with calcitriol and selected calcitriol analogs. The effect of calcitriol and its derivatives on hepatocellular gene expression and vitamin D receptor (VDR) signaling as well as on replication of HCV were assessed by quantitative PCR, microarray analyses and in silico analyses of ligand-VDR complexes. RESULTS The structurally related vitamin D analogs calcipotriol and tacalcitiol, but not calcitriol itself, suppressed HCV replication in a VDR-dependent manner. Using a residue-interaction network approach we outline structural and functional differences between VDR-ligand complexes. In particular we find characteristics in the VDR structure bound to calcipotriol with distinct local residue interaction patterns that affect key functional residues that pertain to the VDR charge clamp, H397 and F422, a VDR regulatory element for interaction with co-activators and -repressors. As a consequence, we show calcipotriol in comparison to calcitriol to induce stronger regulatory actions on the transcriptome of hepatocytes and macrophages including key antimicrobial peptides. CONCLUSION Calcipotriol induces local structure rearrangements in VDR that could possibly translate into a superior clinical potential to execute important non-classical vitamin D effects such as inhibition of HCV replication.
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Affiliation(s)
- Maged Saleh
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Christoph Welsch
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Chengcong Cai
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Claudia Döring
- Senckenberg Institute of Pathology, Goethe University Hospital, D-60596, Frankfurt a. M., Germany
| | - Jérôme Gouttenoire
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011, Lausanne, Switzerland
| | - Judith Friedrich
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Katrin Haselow
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Christoph Sarrazin
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany; Medical Department II Gastroenterology, Hepatology, Infectiology, Diabetology, St. Josefs-Hospital, D-65189, Wiesbaden, Germany
| | - Klaus Badenhoop
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Darius Moradpour
- Division of Gastroenterology and Hepatology, University Hospital Lausanne, CH-1011, Lausanne, Switzerland
| | - Stefan Zeuzem
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Sabrina Rueschenbaum
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany
| | - Christian M Lange
- Department of Medicine 1, J.W. Goethe University Hospital, D-60590, Frankfurt a.M., Germany.
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Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection. Viruses 2018; 10:v10100531. [PMID: 30274202 PMCID: PMC6212901 DOI: 10.3390/v10100531] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 09/25/2018] [Accepted: 09/27/2018] [Indexed: 02/07/2023] Open
Abstract
Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.
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Walker AJ, Peacock CJ, Pedergnana V, STOP‐HCV Consortium, Irving WL. Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review. J Viral Hepat 2018; 25:442-456. [PMID: 29397014 PMCID: PMC6321980 DOI: 10.1111/jvh.12871] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/02/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients.
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Affiliation(s)
- A. J. Walker
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK,Centre for Evidence Based MedicineDepartment of Primary Care Health SciencesUniversity of OxfordOxfordUK
| | - C. J. Peacock
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
| | - V. Pedergnana
- Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK
| | | | - W. L. Irving
- National Institute for Health research (NIHR) Nottingham Biomedical Research CentreNottingham University Hospitals NHS TrustUniversity of NottinghamNottinghamUK
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Augello G, Balasus D, Fusilli C, Mazza T, Emma MR, Giannitrapani L, Agliastro R, Cervello M, Montalto G. Association Between MICA Gene Variants and the Risk of Hepatitis C Virus-Induced Hepatocellular Cancer in a Sicilian Population Sample. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2018; 22:274-282. [PMID: 29584564 DOI: 10.1089/omi.2017.0215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
There are currently no biomarkers that predict hepatocellular carcinoma (HCC) risk in patients with hepatitis C virus (HCV)-related cirrhosis. We investigated the relationships among major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, plasma levels of soluble MICA (sMICA), and HCC risk in patients with HCV-related HCC. One hundred fifty-four HCV-related HCC patients, 93 HCV-related liver cirrhosis (LC) cases, and 244 healthy controls, all sampled from the native Sicilian population, were genotyped using the KASP™ single-nucleotide polymorphism genotyping method. The MICA rs2596542 polymorphism showed that the G/G genotype was significantly more frequent in HCC than control subjects and LC patients (p < 0.005). For MICA rs2596538 polymorphism, the C allele and C/C genotype were significantly more frequent in HCC than in controls and LC cases (p < 0.005), after controlling for potential confounders. These results demonstrate that MICA rs2596542G/G, and particularly the rs2596538C/C polymorphism, are associated with the risk of developing HCV-related HCC in a Sicilian population sample. Importantly, using a machine learning classifier, we found that "age" and either rs2596542 or rs2596538 were important discriminating factors for patients with LC and HCC. Finally, sMICA levels significantly increased during HCV-related liver disease progression, while a significant relationship between both rs2596542 and rs2596538 genotypes and sMICA plasma levels was identified in patients with LC and HCC. In summary, the MICA rs2596538 and rs2596542 variants warrant further research for their clinical validity and utility in relationship to the risk of developing HCV-related HCC in independent populations.
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Affiliation(s)
- Giuseppa Augello
- 1 Institute of Biomedicine and Molecular Immunology "Alberto Monroy ," National Research Council (CNR), Palermo, Italy .,2 Biomedical Department of Internal Medicine and Specialties, University of Palermo , Palermo, Italy
| | - Daniele Balasus
- 1 Institute of Biomedicine and Molecular Immunology "Alberto Monroy ," National Research Council (CNR), Palermo, Italy .,2 Biomedical Department of Internal Medicine and Specialties, University of Palermo , Palermo, Italy
| | - Caterina Fusilli
- 3 Bioinformatics Unit, Casa Sollievo della Sofferenza Hospital , IRCCS, S. Giovanni Rotondo, Italy
| | - Tommaso Mazza
- 3 Bioinformatics Unit, Casa Sollievo della Sofferenza Hospital , IRCCS, S. Giovanni Rotondo, Italy
| | - Maria Rita Emma
- 1 Institute of Biomedicine and Molecular Immunology "Alberto Monroy ," National Research Council (CNR), Palermo, Italy
| | - Lydia Giannitrapani
- 2 Biomedical Department of Internal Medicine and Specialties, University of Palermo , Palermo, Italy
| | - Rosalia Agliastro
- 4 Immunohematology and Transfusion Medicine Unit, "Civico" Regional Hospital , Palermo, Italy
| | - Melchiorre Cervello
- 1 Institute of Biomedicine and Molecular Immunology "Alberto Monroy ," National Research Council (CNR), Palermo, Italy
| | - Giuseppe Montalto
- 1 Institute of Biomedicine and Molecular Immunology "Alberto Monroy ," National Research Council (CNR), Palermo, Italy .,2 Biomedical Department of Internal Medicine and Specialties, University of Palermo , Palermo, Italy
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38
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Liang L, Xu J, Wang M, Xu G, Zhang N, Wang G, Zhao Y. LncRNA HCP5 promotes follicular thyroid carcinoma progression via miRNAs sponge. Cell Death Dis 2018; 9:372. [PMID: 29515098 PMCID: PMC5841368 DOI: 10.1038/s41419-018-0382-7] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 01/22/2018] [Accepted: 02/05/2018] [Indexed: 12/21/2022]
Abstract
Long non-coding RNAs (lncRNAs), which are important functional regulators in cancer, have received increased attention in recent years. In this study, next-generation sequencing technology was used to identify aberrantly expressed lncRNAs in follicular thyroid carcinoma (FTC). The long non-coding RNA-HLA complex P5 (HCP5) was found to be overexpressed in FTC. The results of the qPCR analysis were consistent with the sequencing results. In addition, functional experiments showed that overexpression of HCP5 can promote the proliferation, migration, invasiveness and angiogenic ability of FTC cells. Furthermore, according to the sequencing results, HCP5 and alpha-2, 6-sialyltransferase 2 (ST6GAL2) were co-expressed in FTC. We hypothesised that ST6GAL2 may be regulated by HCP5, which would in turn mediate the activity of FTC cells. Through qPCR, immunostaining analyses and functional experiments, we determined that the expression of HCP5 was elevated and was correlated with the levels of ST6GAL2 in FTC tissues and cells. Mechanistic experiments showed that HCP5 functions as a competing endogenous RNA (ceRNA) and acts as a sponge for miR-22-3p, miR-186-5p and miR-216a-5p, which activates ST6GAL2. In summary, our study revealed that HCP5 is a tumour regulator in the development of FTC and that it may contribute to improvement of FTC diagnosis and therapy.
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Affiliation(s)
- Leilei Liang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Jingchao Xu
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Meng Wang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Gaoran Xu
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Ning Zhang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China
| | - Guangzhi Wang
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China.
| | - Yongfu Zhao
- Department of General Surgery, The Second Hospital of Dalian Medical University, Dalian, China.
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39
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Lee MH, Huang YH, Chen HY, Khor SS, Chang YH, Lin YJ, Jen CL, Lu SN, Yang HI, Nishida N, Sugiyama M, Mizokami M, Yuan Y, L'Italien G, Tokunaga K, Chen CJ. Human leukocyte antigen variants and risk of hepatocellular carcinoma modified by hepatitis C virus genotypes: A genome-wide association study. Hepatology 2018; 67:651-661. [PMID: 28921602 DOI: 10.1002/hep.29531] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 09/06/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022]
Abstract
We conducted a genome-wide association study to discover genetic variants associated with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). We genotyped 502 HCC cases and 749 non-HCC controls using the Axiom-CHB genome-wide array. After identifying single-nucleotide polymorphism clusters located in the human leukocyte antigen (HLA) region which were potentially associated with HCC, HLA-DQB1 genotyping was performed to analyze 994 anti-HCV seropositives collected in the period 1991-2013 in a community-based cohort for evaluating long-term predictability of HLA variants for identifying the risk of HCC. Cox proportional hazards models were used to estimate the hazard ratios and 95% confidence intervals of HLA genotypes for determining the aforementioned HCC risk. Eight single-nucleotide polymorphisms in the proximity of HLA-DQB1 were associated with HCC (P < 8.7 × 10-8 ) in the genome-wide association study. Long-term follow-up showed a significant association with HLA-DQB1*03:01 and DQB1*06:02 (P < 0.05). The adjusted hazard ratios associated with HCC were 0.45 (0.30-0.68) and 2.11 (1.34-3.34) for DQB1*03:01 and DQB1*06:02, respectively. After stratification by HCV genotypes, DQB1*03:01 showed protective effects only in patients with HCV genotype 1, whereas DQB1*06:02 conferred risk of HCC only in patients with HCV non-1 genotypes. HLA imputation analyses revealed that HLA-DRB1*15:01, which is in linkage disequilibrium with DQB1*06:02, also increased the risk of HCC (odds ratio, 1.96; 95% confidence interval, 1.31-2.93). Haplotype analysis supported that DQB1*03:01 and DQB1*06:02 are primarily protective and susceptible variants, respectively. Conclusion: HLA-DQB1 was independently associated with HCC; HCV genotypes modified the effects of HLA-DQB1 on the risk of HCC. (Hepatology 2018;67:651-661).
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Affiliation(s)
- Mei-Hsuan Lee
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Yu-Han Huang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hsuan-Yu Chen
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Seik-Soon Khor
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Toyo, Japan
| | - Ya-Hsuan Chang
- Institute of Statistical Science, Academia Sinica, Taipei, Taiwan
| | - Yu-Ju Lin
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chin-Lan Jen
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Sheng-Nan Lu
- Department of Gastroenterology, Chang-Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Hwai-I Yang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Nao Nishida
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masaya Sugiyama
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Yong Yuan
- World Wide Health Economics and Outcomes Research, Bristol-Myers Squibb, Princeton, NJ
| | | | - Katsushi Tokunaga
- Department of Human Genetics, Graduate School of Medicine, the University of Tokyo, Toyo, Japan
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40
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Matsuura K, Tanaka Y. Host genetic variations associated with disease progression in chronic hepatitis C virus infection. Hepatol Res 2018; 48:127-133. [PMID: 29235266 DOI: 10.1111/hepr.13042] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2017] [Revised: 12/04/2017] [Accepted: 12/05/2017] [Indexed: 12/19/2022]
Abstract
Treatment with recently developed interferon-free oral regimens combining direct-acting antiviral agents (DAAs) results in the elimination of hepatitis C virus (HCV) in almost all chronic hepatitis C (CHC) patients. In the era of DAAs, surveillance of hepatocellular carcinoma (HCC) after eradication of HCV by anti-HCV therapy is particularly important. As is well known, an advanced state of hepatic fibrosis is the major risk factor for developing HCC. Therefore, an increased understanding of various factors associated with disease progression and development of HCC in CHC patients is essential for implementing personalized treatment and surveillance of disease progression and HCC. Recent genome-wide association studies (GWAS) have identified several host genetic variants influencing treatment efficacy or clinical course in HCV infection. This review focuses on these host genetic variations recently identified, mainly by GWAS, which are associated with the clinical course of chronic HCV infection, especially disease progression and hepatocarcinogenesis.
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Affiliation(s)
- Kentaro Matsuura
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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41
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Hai H, Tamori A, Thuy LTT, Yoshida K, Hagihara A, Kawamura E, Uchida-Kobayashi S, Morikawa H, Enomoto M, Murakami Y, Kawada N. Polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with chronic hepatitis C-related hepatocellular carcinoma. Sci Rep 2017; 7:11912. [PMID: 28928439 PMCID: PMC5605683 DOI: 10.1038/s41598-017-10363-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Accepted: 08/09/2017] [Indexed: 12/21/2022] Open
Abstract
Recently, the MICA rs2596542 and DEPDC5 rs1012068 variants in Japanese individuals as well as the HCP5 rs2244546 and PNPLA3 rs738409 variants in European individuals have been found associated with hepatocellular carcinoma (HCC). The present study determined which single nucleotide polymorphism (SNP) is the most predictive for developing hepatitis C virus (HCV)-related HCC in a Japanese cohort. Of the 4 SNPs analysed, only the MICA genotypes were significantly associated with development of HCC (p = 0.0185). The major (MA), hetero (HE), and minor (MI) genotypes occurred in 40%, 41%, and 19% of HCC patients and in 43%, 47%, and 10% of non-HCC patients, respectively. Interestingly, the MICA genotype was significantly correlated with MICA mRNA and soluble protein levels. In patients older than 70 years, the MI genotype was significantly associated with HCC development. In addition, the MI genotype was related to HCC development when the platelet count range was 10-15 × 104/μL, corresponding with the fibrosis stage; but not when the range was less than 10, indicating advanced fibrosis; or greater than 15 × 104/μL, as mild fibrosis. Thus, polymorphisms in MICA, but not in DEPDC5, HCP5 or PNPLA3, are associated with HCC development in Japanese patients with chronic HCV infection.
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Affiliation(s)
- Hoang Hai
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | - Le Thi Thanh Thuy
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kanako Yoshida
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Atsushi Hagihara
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Etsushi Kawamura
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | | | - Hiroyasu Morikawa
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yoshiki Murakami
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Norifumi Kawada
- Department of Hepatology, Osaka City University Graduate School of Medicine, Osaka, Japan
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42
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Clinical significance of SNP (rs2596542) in histocompatibility complex class I-related gene A promoter region among hepatitis C virus related hepatocellular carcinoma cases. J Adv Res 2017; 8:343-349. [PMID: 28417047 PMCID: PMC5388909 DOI: 10.1016/j.jare.2017.03.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Revised: 03/13/2017] [Accepted: 03/16/2017] [Indexed: 12/16/2022] Open
Abstract
The major histocompatibility complex class I-related gene A (MICA) is an antigen induced by stress and performs an integral role in immune responses as an anti-infectious and antitumor agent. This work was designed to investigate whether (SNP) rs2596542C/T in MICA promoter region is predictive of liver cirrhosis (LC) and hepatocellular carcinoma (HCC) or not. Forty-seven healthy controls and 94 HCV-infected patients, subdivided into 47 LC and 47 HCC subjects were enrolled in this study. SNP association was studied using real time PCR and soluble serum MICA concentration was measured using ELISA. Results showed that heterozygous genotype rs2596542CT was significantly (P = 0.022) distributed between HCC and LC related CHC patients. The sMICA was significantly higher (P = 0.0001) among HCC and LC. No significant association (P = 0.56) between rs2596542CT genotypes and sMICA levels was observed. Studying SNP rs2596542C/T association with HCC and LC susceptibility revealed that statistical significant differences (P = 0.013, P = 0.027) were only observed between SNP rs2596542C/T and each of HCC and LC, respectively, versus healthy controls, indicating that the rs2596542C/T genetic variation is not a significant contributor to HCC development in LC patients. Moreover, the T allele was considered a risk factor for HCC and LC vulnerability in HCV patients (OR = 1.93 and 2.1, respectively), while the C allele contributes to decreasing HCC risk. Therefore, SNP (rs2596542C/T) in MICA promoter region and sMICA levels might be potential useful markers in the assessment of liver disease progression to LC and HCC.
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Abstract
Liver-related morbidity and mortality is expanding in people living with HIV. Hepatocellular carcinoma (HCC), the third most lethal malignancy on a global scale, is a dominant complication of chronic liver disease and cirrhosis in patients with coexisting hepatitis. HIV infection further complicates the clinical heterogeneity of HCC, posing concurrent challenges stemming from the underlying immunological status of the patients and the ongoing need for combined antiretroviral therapy. In this article, we review the multiple clinical implications that characterize the multidisciplinary management of HCC in the context of HIV infection.
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Zhu H, Wu J, Shen X. Genome-wide association study: new genetic insights into HBV/HCV-related hepatocellular carcinoma genomes. Scand J Gastroenterol 2017; 52:209-215. [PMID: 27797287 DOI: 10.1080/00365521.2016.1245778] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third common cause of cancer-related death with highest prevalence in developing countries, such as Southeast China and Saharan African. The major pathogenic factors can be categorized into environmental effects and genetic variations, and it is mostly caused by hepatitis B or C virus (HBV and HCV). The geographic prevalence of chronic hepatitis B and C (CHB and CHC) varies, with HBV heavily-infected in developing countries and HCV prevalent in developed countries. The infection of either hepatitis virus B or C causes damage to the liver cells through cellular immune attack by the mechanism of inflammation. However, how liver cell injury progresses to HCC development is still poorly understood. Along with the maturation of genome-wide association study (GWAS) technology, the specific genetic mutations responsible for the progression from CHB or CHC to HCC have been identified. Moreover, the findings of similar studies for these variants are different from each other due to diverse populations. More functional experiments are warranted to confirm the precise roles of these genetic mutations in the correlations between HBV/HCV and HCC for the future clinical application.
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Affiliation(s)
- Hairong Zhu
- a Department of Gastroenterology , Fudan University Affiliated Zhongshan Hospital , Shanghai , China
| | - Jian Wu
- b Shanghai Institute of Liver Disease, Fudan University Affiliated Zhongshan Hospital , Shanghai , China.,c Department of Medical Microbiology, Key Laboratory of Molecular Virology , Fudan University Shanghai Medical College , Shanghai , China
| | - Xizhong Shen
- a Department of Gastroenterology , Fudan University Affiliated Zhongshan Hospital , Shanghai , China.,b Shanghai Institute of Liver Disease, Fudan University Affiliated Zhongshan Hospital , Shanghai , China
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Liu X, Yu L, Han C, Lu S, Zhu G, Su H, Qin W, Liao X, Peng T. Polymorphisms of HLA-DQB1 predict survival of hepatitis B virus-related hepatocellular carcinoma patients receiving hepatic resection. Clin Res Hepatol Gastroenterol 2016; 40:739-747. [PMID: 27288300 DOI: 10.1016/j.clinre.2016.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Revised: 04/10/2016] [Accepted: 04/13/2016] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Human leukocyte antigen (HLA)-DQB1 genetic polymorphisms are associated with an increased risk of hepatitis B virus-related hepatocellular carcinoma (HBV-related HCC). We aimed to evaluate the influence of genetic polymorphisms in HLA-DQB1 exon region and neighboring single nucleotide polymorphisms (SNPs rs9275572 and rs2244546) on survival of HBV-related HCC patients undergoing hepatic resection. METHODOLOGY All SNPs were genotyped by sequencing DNA isolated from tumor samples of 483 patients with HBV-related HCC. RESULTS We identified rs9275572 and HLA-DQB1 haplotype CCCCC (constituted by rs1130375C, rs12722107C, rs12722106C, rs36222416C and rs3189152C) were significantly associated with overall survival (OS) of HBV-related HCC patients (P=0.015 and 0.049, respectively), after adjusting for serum AFP level, the Barcelona Clinic Liver Cancer (BCLC) stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment. In stratified analyses, the AG/GG genotype of rs9275572 significantly decreased risk of death among patients with younger age, serum AFP levels ≥400ng/mL, tumor size ≥10cm, BCLC stage A and radical hepatic resection. HLA-DQB1 haplotype CCCCC was significantly protective for male patients, patients with serum AFP levels <400ng/mL, tumor size ≥10cm, BCLC stage B/C, postoperative adjuvant TACE/TAC/TAE, radical hepatic resection and patients with adjuvant antiviral treatment. Moreover, gene-dosage effects were also observed, patients with SNP rs9275572 AG/GG genotypes and Block2 CCCCC haplotype had a decreased risk of death compared to others after adjusting for serum AFP level, BCLC stages, Child-Pugh score, regional invasion, radical hepatic resection and adjuvant antiviral treatment (adjusted HR=0.38, 95% CI=0.20-0.73, P=0.004). CONCLUSIONS The AG/GG genotype of rs9275572 and HLA-DQB1 Block2 CCCCC haplotype may have protective effects in HBV-related HCC patients receiving hepatic resection.
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Affiliation(s)
- Xiaoguang Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Long Yu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Sichong Lu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Hao Su
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Guangxi Medical University, Nanning, 530021 Guangxi Province, China.
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Ulveling D, Le Clerc S, Cobat A, Labib T, Noirel J, Laville V, Coulonges C, Carpentier W, Nalpas B, Heim MH, Poynard T, Cerny A, Pol S, Bochud PY, Dabis F, Theodorou I, Lévy Y, Salmon D, Abel L, Dominguez S, Zagury JF. A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus-coinfected patients. Hepatology 2016; 64:1462-1472. [PMID: 27339598 DOI: 10.1002/hep.28695] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 05/24/2016] [Accepted: 06/11/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome-wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well-characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome-wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single-nucleotide polymorphisms. Single-nucleotide polymorphisms with P values <10-6 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome-wide significance (P < 5 × 10-8 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 (P = 3.8 × 10-9 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single-nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure (CAV3) or HCV replication (RAD18). The second signal, obtained with rs11790131 (P = 9.3 × 10-9 ) on chromosome region 9p22, was not replicated. CONCLUSION This genome-wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (Hepatology 2016;64:1462-1472).
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Affiliation(s)
- Damien Ulveling
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Sigrid Le Clerc
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Aurélie Cobat
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France
| | - Taoufik Labib
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Josselin Noirel
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Vincent Laville
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Cédric Coulonges
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France
| | - Wassila Carpentier
- Plateforme Post-Génomique P3S, AP-HP, UPMC Université Paris 6, Faculté de Médecine Pitié Salpétrière, Paris, France
| | - Bertrand Nalpas
- Département d'Hépatologie, Hôpital Cochin (AP-HP), Université Paris Descartes, Paris, France
| | - Markus H Heim
- Department of Gastroenterology, University Hospital, Basel, Switzerland
| | - Thierry Poynard
- Université Pierre et Marie Curie, Service d'Hépato-gastroentérologie, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France
| | | | - Stanislas Pol
- Département d'Hépatologie, Hôpital Cochin (AP-HP), Université Paris Descartes, Paris, France.,INSERM UMS20, Institut Pasteur, Paris, France
| | - Pierre-Yves Bochud
- Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland
| | - François Dabis
- Centre de Recherche INSERM U897, Epidemiologie-Biostatistique, Institut de Santé Publique, Epidémiologie et Développement, Université de Bordeaux, Bordeaux, France
| | - Ioannis Theodorou
- Laboratory of Immunity and Infection, Centre d'Immunologie et des Maladies Infectieuses de Paris (CIMI), INSERM U1135, Hôpital Pitié-Salpêtrière (AP-HP), Paris, France.,Plateforme Génomique INSERM-ANRS, Groupe Hospitalier Pitié Salpétrière, AP-HP, UPMC Université Paris 6, Paris, France
| | - Yves Lévy
- INSERM U955, AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie Clinique, Créteil, France
| | - Dominique Salmon
- Department of Infectious Diseases, Cochin Hospital, Paris, France
| | - Laurent Abel
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale (INSERM) U1163, Paris, France.,Paris Descartes University, Imagine Institute, Paris, France.,St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY
| | - Stéphanie Dominguez
- INSERM U955, AP-HP, Groupe Henri-Mondor Albert-Chenevier, Immunologie Clinique, Créteil, France.
| | - Jean-François Zagury
- Équipe Génomique, Bioinformatique et Applications (EA4627), Chaire de Bioinformatique, Conservatoire National des Arts et Métiers, Paris, France.
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Bandiera S, Billie Bian C, Hoshida Y, Baumert TF, Zeisel MB. Chronic hepatitis C virus infection and pathogenesis of hepatocellular carcinoma. Curr Opin Virol 2016; 20:99-105. [PMID: 27741441 DOI: 10.1016/j.coviro.2016.09.010] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Revised: 09/20/2016] [Accepted: 09/23/2016] [Indexed: 02/07/2023]
Abstract
Hepatitis C virus (HCV) infection is one of the major causes of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. While the knowledge about the molecular virology of HCV infection has markedly advanced, the molecular mechanisms of disease progression leading to fibrosis, cirrhosis and HCC are still unclear. Accumulating experimental and clinical studies indicate that HCV may drive hepatocarcinogenesis directly via its proteins or transcripts, and/or indirectly through induction of chronic liver inflammation. Despite the possibility to eradicate HCV infection through direct-acting antiviral treatment, the risk of HCC persists although specific biomarkers to estimate this risk are still missing. Thus, a better understanding of HCV-induced HCC and more physiological liver disease models are required to prevent cancer development.
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Affiliation(s)
- Simonetta Bandiera
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France
| | - C Billie Bian
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Yujin Hoshida
- Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
| | - Mirjam B Zeisel
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France; Université de Strasbourg, Strasbourg, France.
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48
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Molecular mechanisms of hepatitis C virus-induced hepatocellular carcinoma. Clin Microbiol Infect 2016; 22:853-861. [PMID: 27476823 DOI: 10.1016/j.cmi.2016.07.019] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Revised: 07/09/2016] [Accepted: 07/16/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is a major leading cause of hepatocellular carcinoma (HCC). HCV-induced hepatocarcinogenesis is a multistep process resulting from a combination of pathway alterations that are either caused directly by viral factors or immune mediated as a consequence of a chronic state of inflammation. Host genetic variation is now emerging as an additional element that contribute to increase the risk of developing HCC. The advent of direct-acting antiviral agents foresees a rapid decline of HCC rate in HCV patients. However, a full understanding of the HCV-mediated tumourigenic process is required to elucidate if pro-oncogenic signatures may persist after virus clearance, and to identify novel tools for HCC prevention and therapy. In this review, we summarize the current knowledge of the molecular mechanisms responsible for HCV-induced hepatocarcinogenesis.
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49
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Alberti A, Lacoin L, Morais E, Lefevre C, Abogunrin S, Iheanacho I. Literature review of the distribution of hepatitis C virus genotypes across Europe. J Med Virol 2016; 88:2157-2169. [DOI: 10.1002/jmv.24573] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/10/2016] [Indexed: 12/21/2022]
Affiliation(s)
- Alfredo Alberti
- Department of Molecular Medicine; University of Padova; Padua Italy
| | | | - Edith Morais
- Bristol-Myers Squibb; Rueil-Malmaison; Paris France
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50
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Role of HCP5-miR-139-RUNX1 Feedback Loop in Regulating Malignant Behavior of Glioma Cells. Mol Ther 2016; 24:1806-1822. [PMID: 27434586 DOI: 10.1038/mt.2016.103] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2015] [Accepted: 05/01/2016] [Indexed: 02/07/2023] Open
Abstract
Aberrant expression of long noncoding RNAs has recently been reported in tumorigenesis and plays a pivotal role in regulating malignant behavior of cancers. In this study, we confirmed that the long noncoding RNAs human histocompatibility leukocyte antigen (HLA) complex P5 (HCP5) was up-regulated in glioma tissues as well as in U87 and U251 cells. Knockdown of HCP5 inhibited the malignant biological behavior of glioma cells by reducing proliferation, migration and invasion, and inducing apoptosis. HCP5 regulated the malignant behavior of glioma cells by binding to microRNA-139, which functions as a tumor suppressor. Moreover, knockdown of HCP5 down-regulated Runt-related transcription factor 1, a direct and functional downstream target of microRNA-139 that is involved in microRNA-139-mediated tumor-suppressive effects in glioma cells. Runt-related transcription factor 1 increased promoter activities and upregulated expression of the oncogenic gene astrocyte elevated gene-1 (AEG-1). Runt-related transcription factor 1 also increased the promoter activities and expression of HCP5, which showed a positive feedback loop in regulating the malignant behavior of glioma cells. In conclusion, this study demonstrated that the HCP5-microRNA-139- Runt-related transcription factor 1 feedback loop plays a pivotal role in regulating the malignant behavior of glioma cells, which may provide a potential therapeutic strategy for treating glioma.
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