HBx-induced upregulation of MAP1S drives hepatocellular carcinoma proliferation and migration via MAP1S/Smad/TGF-β1 loop.

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), has a significantly higher risk of recurrence. However, the exact mechanism by which HBV prompts HCC recurrence remains largely unknown. In this study liver microarray test revealed significant upregulation of microtubule associated protein 1S (MAP1S) in metastatic HCC compared to control. MAP1S knockdown suppressed growth of HCCLM3 cells in vitro and in vivo. Mechanistically, HBV-encoded X protein (HBx) upregulates MAP1S, which enhances microtubule (MT) acetylation by promoting the degradation of histone deacetylase 6 (HDAC6), and facilitates the nuclear translocation of Smad complex, and thereby enhancing downstream TGF-β signaling. Smad complex, in turn, increases MAP1S, establishing a feedback loop of MAP1S/Smad/TGF-β1. Finally, survival analysis of 150 HBV-associated HCC patients demonstrated both increased MAP1S and decreased HDAC6 were significantly associated with shorter relapse-free survival. Collectively, this study reveals a unique mechanism whereby HBx-induced upregulation of MAP1S drives HBV-related HCC proliferation and migration through the MAP1S/Smad/TGF-β1 feedback loop. TEASER: MAP1S is a key link between HBV infection and a higher risk of metastatic recurrence of HCC.