Hepatitis B/C viruses upregulate TNNT1 expression to induce epithelial-mesenchymal transition and hepatocellular carcinogenesis via MTA2

Abstract

Hepatitis B and C viruses (HBV and HCV) infection has been considered as a major cause of hepatocellular carcinoma (HCC). Although tremendous efforts have been made to understand HBV/HCV-induced tumorigenicity, the precise mechanism and the critical host factors involved HBV/HCV infection-induced HCC remain to be explored. Here, we found troponin T (TNNT1) expression was significantly upregulated in HBV/HCV-infected hepatoma cells, HCC tissues, and mouse models. HBV/HCV-induced TNNT1 binds metastasis-associated protein 2 (MTA2), causing lysosomal dysfunction and autophagy suppression, which subsequently leads to increased proliferation and epithelial-mesenchymal transition (EMT) of HCC. MTA2 promotes TNNT1 deacetylation and protects TNNT1 from ubiquitination degradation, thereby enhances TNNT1 stability and carcinogenesis effect in both cellular and mouse models. TNNT1 troponin 10-aa peptide T10 can block TNNT1-MTA2 interaction and MTA2-mediated TNNT1 deacetylation, and thus promote autophagy and suppress cell proliferation/EMT. TNNT1 troponin T10 may be promising for viral HCC therapy.