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HBx-mediated GPT2 suppression promotes liver cancer development by downregulating ADH1A
Hongjuan You1, Xing Wang1,2, Ruyu Liu3
1Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, School of Basic Medical Sciences, Xuzhou Medical University, Xuzhou 221004, China.
Hepatitis B virus X protein hijacks TRIM25 to degrade GPT2, a tumor suppressor, promoting liver cancer by altering metabolism. Restoring GPT2 may offer a new treatment strategy for virus-associated liver cancer.
Area of Science:
- Hepatology
- Oncology
- Molecular Biology
Background:
- Hepatocellular carcinoma (HCC) is driven by Hepatitis B virus (HBV), involving metabolic reprogramming.
- Mechanisms linking HBV oncoproteins to metabolic changes in HCC are not fully understood.
Purpose of the Study:
- Investigate the role of metabolic enzyme GPT2 in HBV-associated HCC.
- Elucidate GPT2 regulation by HBV X protein (HBx) and its impact on downstream signaling.
Main Methods:
- Analysis of patient cohorts, in vitro/in vivo functional assays.
- Co-immunoprecipitation, ubiquitination assays, and genetic/pharmacological manipulations.
Main Results:
- GPT2 is downregulated in HCC, correlating with poor survival.
- GPT2 loss promotes HCC cell proliferation, migration, and lipid accumulation.
- HBx recruits TRIM25 to degrade GPT2, activating the mTOR-ADH1A-LSD1 axis and promoting lipogenesis.
Conclusions:
- A novel HBx-TRIM25-GPT2-ADH1A-LSD1 signaling axis drives HBV-associated hepatocarcinogenesis.
- GPT2 acts as a metabolic tumor suppressor hijacked by HBV.
- GPT2 is a potential therapeutic target for HBV-associated HCC.
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