Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region

Li, Chiao-Ling; Li, Chenyu; Lin, Yu‐Hui; Ho, Ming‐Chih; Chen, Ding‐Shinn; Chen, Pei‐Jer; Yeh, Shiou–Hwei

doi:10.1002/hep.30201

Cited by 43 publications

(49 citation statements)

References 36 publications

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“…AR signaling is known to be involved in the initiation of carcinogen‐related or hepatitis B virus–related HCC . It has been reported that AR regulates a number of downstream targets, such as enhancer of zeste 2 polycomb repressive complex 2 subunit, mature microRNA 520f, telomerase reverse transcriptase, ETS proto‐oncogene 1 transcription factor, Nanog, reactive oxygen species, and p53, to promote hepatocarcinogenesis. Therefore, it is possible that the combination of FAK plus β‐catenin induces AR to promote the development of HCC.…”

Section: Resultsmentioning

confidence: 99%

Focal Adhesion Kinase and β‐Catenin Cooperate to Induce Hepatocellular Carcinoma

et al. 2019

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There is an urgent need to understand the molecular signaling pathways that drive or mediate the development of hepatocellular carcinoma (HCC). The focal adhesion kinase (FAK) gene protein tyrosine kinase 2 is amplified in 16.4% of The Cancer Genome Atlas HCC specimens, and its amplification leads to increased FAK mRNA expression. It is not known whether the overexpression of FAK alone is sufficient to induce HCC or whether it must cooperate in some ways with other oncogenes. In this study, we found that 34.8% of human HCC samples with FAK amplification also show β-catenin mutations, suggesting a co-occurrence of FAK overexpression and β-catenin mutations in HCC. We overexpressed FAK alone, constitutively active forms of β-catenin (CAT) alone, or a combination of FAK and CAT in the livers of C57/BL6 mice. We found that overexpression of both FAK and CAT, but neither FAK nor CAT alone, in mouse livers was sufficient to lead to tumorigenesis. We further demonstrated that FAK's kinase activity is required for FAK/CAT-induced tumorigenesis. Furthermore, we performed RNA-sequencing analysis to identify the genes/signaling pathways regulated by FAK, CAT, or FAK/CAT. We found that FAK overexpression dramatically enhances binding of β-catenin to the promoter of androgen receptor (AR), which leads to increased expression of AR in mouse livers. Moreover, ASC-J9, an AR degradation enhancer, suppressed FAK/ CAT-induced HCC formation. Conclusion: FAK overexpression and β-catenin mutations often co-occur in human HCC tissues. Co-overexpression of FAK and CAT leads to HCC formation in mice through increased expression of AR; this mouse model may be useful for further studies of the molecular mechanisms in the pathogenesis of HCC and could lead to the identification of therapeutic targets.

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Section: Resultsmentioning

confidence: 99%

Focal Adhesion Kinase and β‐Catenin Cooperate to Induce Hepatocellular Carcinoma

et al. 2019

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“…Notably, however, the tumour tissue from patient 2 contained 34 unique HBV integrations, of which a few predominated, probably as the result of mono/oligoclonal expansion 34 . Also, the HBV integration with the second highest coverage was found in TERT , an oncogene previously associated with HBV‐induced HCC 35,36 . The expression of TERT was 1000‐fold compared with healthy liver tissue.…”

Section: Discussionmentioning

confidence: 98%

Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA

Ringlander

Skoglund

Prakash

et al. 2020

Journal of Viral Hepatitis

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“…Meanwhile, Prieto J proposed that the estrogen-mediated inhibition of IL-6 production by Kupffer cells (KCs) reduced HCC risk in females, and that these findings could be used to prevent HCC in males [19] . Furthermore, Montella M et al and Li, C et al found that androgens promoted the increased transcription and replication of HBV genes in HBV-related HCC patients by stimulating its signaling pathway, and that estrogen could play a protective role against the progression of HBV infections by decreasing HBV RNA transcription and inflammatory cytokine production [20][21] . In our study, young female patients (< 50 years) showed lower HCC incidence rates, which could be due to the protective effect of estrogen.…”

Section: Discussionmentioning

confidence: 99%

Impact of gender as a prognostic factor in HBV-related Hepatocellular Carcinoma: the survival strength of female patients in BCLC stage 0-B

Yu¹,

Liu²,

Wang³

et al. 2019

J. Cancer

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Background and Aims: Although previous studies suggested that female patients who underwent curative resection in early-stage hepatocellular carcinoma (HCC) had better survival rates than male patients, it is unclear whether females in different HCC stages actually have survival advantage. This study aimed to investigate whether gender differences in the Barcelona Clinic Liver Cancer (BCLC) classification system contributed to different survival outcomes in hepatitis B virus (HBV)-related HCC. Methods: A retrospective analysis was performed of 1,753 patients diagnosed with HBV-related HCC between January 2008 and June 2017 at the Beijing Ditan hospital. The BCLC stages were classified into BCLC stage 0-B and BCLC stage C-D groups. Factors determining overall survival (OS) and progression-free survival (PFS) were analyzed via univariate and multivariate analysis using the Kaplan-Meier method and Cox proportional-hazards regression models. Results: The cohort consisted of 1,202 BCLC stage 0-B and 551 BCLC stage C-D HBV-related HCC patients. Gender was identified to be an independent risk factor for OS (HR = 0.617; 95% CI, 0.426-0.895; p = 0.011) and PFS (HR = 0.728; 95% CI, 0.558-0.950; p = 0.019) in BCLC stage 0-B HBV-related HCC patients. With respect to OS and PFS, there were significant differences between female and male patients only in BCLC stage 0-B, but not in BCLC stage C-D. The OS and PFS in BCLC stage 0-B for female patients was significantly greater than that for male patients (p = 0.0103, p = 0.0112). Tumor multiplicity and size were independent risk factors for female patients in BCLC stage 0-B, whereas tumor multiplicity, tumor size, HBV-DNA, hemoglobin, total bilirubin, and alpha-fetoprotein levels were independent risk factors for male patients in BCLC stage 0-B. Conclusions: Different outcomes in OS or PFS with respect to gender only exist in BCLC stage 0-B HBV-related HCC patients. Female patients have a better outcome than male patients in BCLC stage 0-B.

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Androgen Receptor Enhances Hepatic Telomerase Reverse Transcriptase Gene Transcription After Hepatitis B Virus Integration or Point Mutation in Promoter Region

Abstract: TERT elevation by AR via integrated HBV and point mutation at TERT promoter region was identified as a new mechanism for the male dominance of HBV-related HCCs. Telomerase and AR thus become new targets for intervention of HCC. This article is protected by copyright. All rights reserved.

Cited by 43 publications

References 36 publications

Focal Adhesion Kinase and β‐Catenin Cooperate to Induce Hepatocellular Carcinoma

Focal Adhesion Kinase and β‐Catenin Cooperate to Induce Hepatocellular Carcinoma

Deep sequencing of liver explant transcriptomes reveals extensive expression from integrated hepatitis B virus DNA

Impact of gender as a prognostic factor in HBV-related Hepatocellular Carcinoma: the survival strength of female patients in BCLC stage 0-B

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