EIF4G2 Promotes Hepatocellular Carcinoma Progression via IRES-dependent PLEKHA1 Translation Regulation

Hepatocellular
carcinoma (HCC) is a highly lethal cancer,
and proteomic
studies have shown increased protein diversity and abundance in HCC
tissues, whereas the role of protein translation has not been extensively
explored in HCC. Our research focused on key molecules in the translation
process to identify a potential contributor in HCC. We discovered
that EIF4G2, a crucial translation initiation factor, is significantly
upregulated in HCC tissues and associated with poor prognosis. This
study uniquely highlights the impact of EIF4G2 deletion, which suppresses
tumor growth and metastasis both in vitro and in vivo. Furthermore, polysome analysis and nascent protein
synthesis assays revealed EIF4G2’s role in regulating protein
translation, specifically identifying PLEKHA1 as a key translational
product. This represents a novel mechanistic insight into HCC malignancy.
RNA immunoprecipitation (RIP) and Dual-luciferase reporter assays
further revealed that EIF4G2 facilitates PLEKHA1 translation via an
IRES-dependent manner. Importantly, the synergistic effects of EIF4G2
depletion and PLEKHA1 reduction in inhibiting cell migration and invasion
underscore the therapeutic potential of targeting this axis. This
study not only advances our understanding of translational regulation
in HCC but also identifies the EIF4G2-PLEKHA1 axis as a promising
therapeutic target, offering new avenues for intervention in HCC treatment.