LncRNA GAS6-AS2 facilitates tumor growth and metastasis of hepatocellular carcinoma by activating the PI3K/AKT/FoxO3a signaling pathway

Abstract

The morbidity and mortality of hepatocellular carcinoma (HCC) are growing yearly. Several reports emphasize the importance of long non-coding RNAs (lncRNAs) in HCC. This paper provides a molecular mechanism for the function of GAS6-AS2 in HCC. The expressions of GAS6-AS2, miR-493-5p and OTUB1 were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell proliferation, apoptosis, migration, and invasion were measured by cell counting kit-8 (CCK-8), flow cytometry and transwell assay, respectively. The interaction of miR-493-5p and GAS6-AS2 or OTU domain-containing Ubiquitin Aldehyde-binding Protein 1 (OTUB1) was analyzed by starBase v2.0 and verified by luciferase reporter assay. The protein level of OTUB1 as well as PI3K, p-PI3K, AKT, p-AKT, FoxO3a, p-FoxO3a and β-actin protein levels were distinguished by western blot. GAS6-AS2 was up-regulated in HCC tissues and cells. GAS6-AS2 knockdown inhibited proliferation, migration, and invasion but promoted apoptosis. MiR-493-5p, a target of GAS6-AS2, was down-regulated in HCC tissues and cells. Inhibition of miR-493-5p reversed the effects of GAS6-AS2 knockdown on HCC cells. OTUB1, a target of miR-493-5p, was up-regulated in HCC cells and its expression was modulated by miR-493-5p. Overexpression of OTUB1 recovered the positive effects of miR-493-5p enrichment or GAS6-AS2 knockdown on HCC cells. GAS6-AS2 knockdown impeded the activation of PI3K/AKT/FoxO3a signaling pathway, while this activation was reversed by miR-493-5p inhibition or OTUB1 overexpression. In conclusion, GAS6-AS2 knockdown suppressed proliferation, migration, and invasion but promoted apoptosis of HCC cells by impeding PI3K/AKT/FoxO3a signaling pathway through regulating the GAS6-AS2/miR-493-5p/OTUB1 axis.