EIF2B5 promotes malignant progression of hepatocellular carcinoma by activating the PI3K/AKT signaling pathway through targeting RPL6.

Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with limited treatment options and poor prognosis. In this study, we demonstrated the critical role of EIF2B5 in driving HCC progression. We found EIF2B5 expression is significantly upregulated in HCC tumor tissues in several bioinformatics datasets, including The Cancer Genome Atlas, and that high expression of EIF2B5 predicts poor prognosis for HCC patients. Through a series of in vitro cell biology experiments, we found that EIF2B5 knockdown significantly attenuated Hep3B and HepG2 proliferation, migration, and invasion and increased cell cycle arrest, whereas EIF2B5 overexpression promoted HCC progression. Through mass spectrometry and immunoprecipitation validation, we found that EIF2B5 directly interacted with RPL6 and that when EIF2B5 was overexpressed in HCC cells, it promoted the expression of the downstream protein RPL6, which was able to activate the phosphatidylinositol kinase (PI3K)/serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway and thereby increase the proliferation and invasion ability of HCC cell lines, as verified by second-generation sequencing analysis and western blot. We further verified these findings using the mouse ectopic tumor assay, and the results showed that EIF2B5 knockdown significantly inhibited tumor progression in HCC mice. The present study suggests that EIF2B5 promotes malignant progression of HCC by interacting with RPL6 and activating the PI3K/AKT/mTOR signaling pathway and may serve as a potential target for the treatment of HCC.