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An Oncogenic Hepatocyte-Induced Orthotopic Mouse Model of Hepatocellular Cancer Arising in the Setting of Hepatic Inflammation and Fibrosis
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Androgen receptor variant 7 exacerbates hepatocarcinogenesis in a c-MYC-driven mouse HCC model
Tatsuo Kido1,2, Yun-Fai Chris Lau3,4,5
1Division of Cell and Developmental Genetics, Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA, USA. Tatsuo.Kido@ucsf.edu.
Oncogenesis
|February 6, 2023
Summary
Androgen receptor variant 7 (AR-V7) worsens liver cancer (HCC) driven by c-MYC. AR-V7 alters metabolism and suppresses a tumor suppressor, contributing to cancer
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen receptor variant 7 (AR-V7) is an androgen-independent isoform of the androgen receptor.
- AR-V7 expression is observed in a subset of hepatocellular carcinoma (HCC) cases, but its function in this disease remains unclear.
- Hepatocellular carcinoma (HCC) is a significant global health concern with complex underlying molecular mechanisms.
Purpose of the Study:
- To investigate the role of AR-V7 in hepatocarcinogenesis using a c-MYC-driven mouse HCC model.
- To elucidate the impact of AR-V7 on gene expression and biological pathways in HCC.
- To understand the interaction between AR-V7, c-MYC, and tumor suppressor genes in HCC development.
Main Methods:
- Generation of a c-MYC-driven mouse HCC model via hydrodynamic tail-vein injection.
- RNA-sequencing (RNA-seq) transcriptome and bioinformatics analyses to assess gene expression changes.
- Investigation of the p53 signaling pathway and Claudin 7 expression in response to AR-V7 and c-MYC.
Main Results:
- AR-V7 significantly exacerbated c-MYC-mediated oncogenesis in mouse HCC livers.
- AR-V7 and c-MYC synergistically altered gene sets involved in lipid and steroid/sterol metabolism.
- AR-V7 suppressed tumor suppressor Claudin 7 expression, while c-MYC upregulated it via the p53 pathway; Claudin 7 overexpression inhibited HCC development.
Conclusions:
- AR-V7 exacerbates c-MYC-driven hepatocarcinogenesis by enhancing oncogenic roles and diminishing anti-oncogenic functions of c-MYC.
- AR-V7 contributes to the inter- and intra-tumor heterogeneity observed in HCC.
- Targeting AR-V7 may offer a therapeutic strategy for specific HCC patient subpopulations.
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