Abstract
Hepatitis B virus (HBV) infection has been proven strongly associated with the initiation and progression of hepatocellular carcinoma (HCC). However, a substantial amount of virally-induced mechanisms that cause malignant transformation in the liver remains largely unexplored, especially for HBV-induced metabolic reprogramming. In the present study, we identified and confirmed the HBV integration breakpoints clustering at the C-terminal X gene is a tumor-specific event, and the C-terminal HBx is expressed more frequently in the tumors than normal liver tissues. Then, the oncogenic effect of the truncated HBx was validated in vitro and in vivo. Transcriptome sequencing revealed that TXNIP, as a downstream target of truncated HBx, negatively regulates glucose metabolism. Screening of public database and our clinical cohort exhibited that TXNIP is significantly down-regulated in HCC patients with truncated HBx expression, compared to those with full-length HBx expression and HBV-negative patients. Lower expression of TXNIP is negatively correlated with patient survival. We also reported evidence that truncated HBx down-regulates TXNIP expression by transactivation via the transcriptional repressor NFACT2. Additionally, the re-introduction of TXNIP inhibited the metabolic reprogramming from mitochondrial respiration to aerobic glycolysis induced by truncated HBx and further resulted in HCC growth arrest in vitro and in vivo. In summary, our finding proposes a promising diagnostic and therapeutic strategy for HBV-induced HCC.
Citation Format: Yu Zhang. Glucose metabolic reprogramming in HBV-related hepatocellular carcinoma through C-terminal truncated HBx protein suppression of TXNIP [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5991.
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