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Hepatitis B Virus X Protein (HBx) Suppresses Transcription Factor EB (TFEB) Resulting in Stabilization of Integrin Beta 1 (ITGB1) in Hepatocellular Carcinoma Cells.

ABSTRACT: Hepatitis B virus (HBV) infection is a major etiological risk for the incidence of hepatocellular carcinoma (HCC), and HBV X protein (HBx) is essential for oncogenic transformation. It is not known that if HBx can sabotage the lysosomal system for transformation and tumorigenesis, or its mechanism if it does have an effect. Examining clinical data, we observed that the downregulation of lysosomal components and transcription factor EB (TFEB) was associated with a poor prognosis of HCC patients. In HCC cells, we found that expression of HBx suppressed TFEB, impaired biogenesis of autophagic-lysosome, and promoted cellular dissemination. HBx mediated downregulation of TFEB led to impairment of autophagic/lysosomal biogenesis and flux, and consequently, accumulation of integrin beta 1 (ITGB1) for motility of HCC cells. Conversely, TFEB, in a steady-state condition, through induction of lysosomal biogenesis restrained ITGB1 levels and limited mobility of HCC cells. Specifically, overexpression of TFEB upregulated and activated the cysteine proteases including cathepsin L (CTSL) to degrade ITGB1. Conversely, expression of cystatin A (CSTA) or cystatin B (CSTB), the cellular inhibitors of lysosomal cysteine proteinases, spared ITGB1 from degradation and promoted dissemination of HCC cells. Taken together, this study suggests a potential mechanism for HBV-mediated malignancy, showing that HBx mediated downregulation of TFEB leads to accumulation of ITGB1 for HCC cell migration.

SUBMITTER: Zhang C

PROVIDER: S-EPMC7967237 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationalePostischemic angiogenesis is critical to limit the ischemic tissue damage and improve the blood flow recovery. The regulation and the underlying molecular mechanisms of postischemic angiogenesis are not fully unraveled. TFEB (transcription factor EB) is emerging as a master gene for autophagy and lysosome biogenesis. However, the role of TFEB in vascular disease is less understood.ObjectiveWe aimed to determine the role of endothelial TFEB in postischemic angiogenesis and its underlying molecular mechanism.Methods and resultsIn primary human endothelial cells (ECs), serum starvation induced TFEB nuclear translocation. VEGF (vascular endothelial growth factor) increased TFEB expression level and nuclear translocation. Utilizing genetically engineered EC-specific TFEB transgenic and KO (knockout) mice, we investigated the role of TFEB in postischemic angiogenesis in the mouse hindlimb ischemia model. We observed improved blood perfusion and increased capillary density in the EC-specific TFEB transgenic mice compared with the wild-type littermates. Furthermore, blood flow recovery was attenuated in EC-TFEB KO mice compared with control mice. In aortic ring cultures, the TFEB transgene significantly increased vessel sprouting, whereas TFEB deficiency impaired the vessel sprouting. In vitro, adenovirus-mediated TFEB overexpression promoted EC tube formation, migration, and survival, whereas siRNA-mediated TFEB knockdown had the opposite effect. Mechanistically, TFEB activated AMPK (AMP-activated protein kinase)-α signaling and upregulated autophagy. Through inactivation of AMPKα or inhibition of autophagy, we demonstrated that the AMPKα and autophagy are necessary for TFEB to regulate angiogenesis in ECs. Finally, the positive effect of TFEB on AMPKα activation and EC tube formation was mediated by TFEB-dependent transcriptional upregulation of MCOLN1 (mucolipin-1).ConclusionsIn summary, our data demonstrate that TFEB is a positive regulator of angiogenesis through activation of AMPKα and autophagy, suggesting that TFEB constitutes a novel molecular target for ischemic vascular disease.

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Hepatitis B Virus X Protein (HBx) Suppresses Transcription Factor EB (TFEB) Resulting in Stabilization of Integrin Beta 1 (ITGB1) in Hepatocellular Carcinoma Cells.

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