HRP-3 protects the hepatoma cells from glucose deprivation-induced apoptosis

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. It is important for HCC cells to resist to apoptosis caused by adverse energy pressure in microenvironment during the HCC tumorigenesis. HRP-3, a member of hepatoma-derived growth factor (HDGF)-related proteins (HRP) family, was shown to be highly up-regulated in HCC tissues and play an important role in HCC pathogenesis based on our previous research. The aim of the study was to investigate the HRP-3's role in HCC cells endurance against energy pressure. Method: The HRP-3 expression level in primary rat hepatocytes and human HCC cell lines were examined when changing the extracellular glucose concentration. To assess biological function of HRP-3 during glucose deprivation, HRP-3 stable knockdown and control clones of SMMC-7721 and SK-hep1 were constructed for further analysis including cellular morphology observation, apoptotic sub G1 peak analysis and the mTOR-mediated phosphorylation of S6K1 detection in the absence of glucose. Results: Expression level of HRP-3 protein was highly up-regulated both in primary rat hepatocytes and HCC cells as prolonging the stimulation of glucose deprivation. Both morphology and sub-G1 phase analyses indicated that stable knockdown of HRP-3 sensitized HCC cells to glucose deprivation-induced cell apoptosis. Furthermore, silence of HRP-3 prevented the de-phosphorylation of S6K1 induced by glucose deprivation, which was an essential molecular event for HCC cell survival in energy pressure. Conclusions: We propose that glucose deprivation-induced HRP-3 up-regulation potentially plays a major role in protecting HCC cells against apoptosis caused by energy pressure.