DDX42 Enhances Hepatocellular Carcinoma Cell Proliferation, Radiation and Sorafenib Resistance via Regulating GRB2 RNA Maturation and Activating PI3K/AKT Pathway

The DEAD-box RNA helicase (DDX) family is one of the canonical splicing regulators, engaged in RNA metabolism, and generally participates in forming spliceosomes. However, systematic analysis of DDX family members in hepatocellular carcinoma (HCC) has not been conducted before, and their biological functions need to be investigated further. Based on biological function enrichment analysis, radiosensitivity index (RSI), and prediction IC50 index for sorafenib, we ultimately ascertain DDX42 as a candidate gene. DDX42 was highly expressed in HCC than in para-tumour tissues and was a prognostic factor for HCC patients. Importantly, DDX42 overexpression promotes cell proliferation, radio-resistance and sorafenib resistance in HCC cells and activates the PI3K/AKT pathway. Knockdown of DDX42 moderately inhibited cell growth of HCC cells and significantly increased radio-sensitivity, enhanced the efficacy of sorafenib, and inactivated the PI3K/AKT pathway. Mechanically, DDX42 could urge the mRNA maturation of GRB2, contributing to cell proliferation and enhancement of resistance ability to radiotherapy and sorafenib for HCC cells. Subcutaneous xenograft nude mouse model showed that DDX42 significantly promoted tumour growth as compared to the control group and lifted the expression of GRB2, KI-67 and PCNA in vivo. In conclusion, our findings facilitate the acknowledgment of tumour initiation and mechanisms of treatment resistance in HCC, and targeting the axis of DDX42 and GRB2 may be promising strategies for synergy with radiotherapy or sorafenib for HCC patients.