14-3-3ζ promotes hepatocellular carcinoma venous metastasis by modulating hypoxia-inducible factor-1α

Portal vein tumor thrombus (PVTT) is a type of intrahepatic metastasis arising from hepatocellular carcinoma (HCC) and is highly correlated with a poor prognosis. Hypoxia is common in solider tumors, including HCC, where it alters the behavior of HCC cells. We asked whether and how hypoxia contributes to PVTT formation. We demonstrated that increased intratumoral hypoxia is strongly associated with PVTT formation in HCC. We also showed that 14-3-3 zeta is induced by hypoxia in HCC cells and correlates with PVTT formation in clinical HCC samples. In addition, 14-3-3 zeta up-regulates HIF-1 alpha expression by recruiting HDAC4, which prevents HIF-1 alpha acetylation, thereby stabilizing the protein. Under hypoxic conditions in vitro, 14-3-3 zeta knockdown inhibits hypoxia-induced HCC invasion by the HIF-1 alpha/EMT pathway. Blockade of 14-3-3 zeta in HCC cells reduces PVTT formation and distant lung metastasis in vivo. Moreover, a combination of 14-3-3 zeta and HIF-1 alpha expression is more prognostic for HCC patients than either protein alone. These results suggest that the hypoxia/14-3-3 zeta/HIF-1 alpha pathway plays an important role in PVTT formation and HCC metastasis.