RASAL1 inhibits HepG2 cell growth via HIF-2α mediated gluconeogenesis.

Abstract

RAS protein activator like 1 (RASAL1) is a member of the RAS GTPase-activating protein (GAP) family, and has been identified as a tumor suppressor in various types of cancer. In the present study, it was determined that decreased levels of RASAL1 were accompanied by a higher pathological stage and larger tumor size in human liver cancer. Therefore, it was hypothesized that RASAL1 may serve an inhibitory role in liver cancer. In the present study, the following was demonstrated: i) Exogenous expression of RASAL1 may inhibit the proliferation and invasion ability of HepG2 cells; ii) overexpression of RASAL1 may downregulate HIF-2α transcription activity and HIF-2α-mediated gluconeogenesis through extracellular signal-related kinase 1/2 activation; iii) RASAL1 may reduce the xenograft tumor size in nude mice by inhibiting the expression of hypoxia-inducible factor (HIF)-2α and gluconeogenesis enzymes. These data suggest that the RASAL1/HIF-2α axis may serve an essential role in the growth of HepG2 cells, and that this signaling cascade may be a novel therapeutic target for the treatment of liver cancer.