DDX18 promotes growth and metastasis of hepatocellular carcinoma via activating EMT and MAPK signaling.

Abstract

Background: DDX18, a member of the DEAD-box RNA helicase family, plays a pivotal role in ribosome biogenesis and RNA metabolism and is thus extensively implicated in tumorigenesis. Although its oncogenic functions have been well-documented across various malignancies, the precise molecular mechanisms underlying DDX18-driven progression in hepatocellular carcinoma (HCC) remain largely undefined. This study systematically elucidates the pathological contributions of DDX18 to HCC through a combination of comprehensive in vitro experiments and in vivo analyses.

Methods: We assessed the expression and effects of DDX18 on HCC tissues and cellular functions through bioinformatics analyses, wound healing assays, colony formation assays, transwell assays, and flow cytometry. Western blot analysis revealed that mitogen-activated protein kinase (MAPK) signaling pathways were associated with protein levels involved in the epithelial-mesenchymal transition (EMT). Co-immunoprecipitation (Co-IP) and immunoFluorescence colocalization experiments confirmed the interaction between DDX18 and REXO4. Additionally, we evaluated the functional roles of DDX18 and REXO4 using a series of in vitro assays and nude mouse xenograft models.

Results: Our data demonstrated elevated expression of DDX18 in HCC tissues. DDX18 significantly increased cell proliferation, invasion, and migration, and activated EMT and MAPK signaling pathways in vitro. Mechanistically, DDX18 interacts with REXO4, thereby promoting tumor growth and metastasis by regulating the EMT process and MAPK signaling. Furthermore, overexpression of REXO4 reversed the inhibitory effects of DDX18 knockdown both in vitro and in vivo.

Conclusions: This study provides evidence that the DDX18/REXO4 axis plays a critical role in HCC development and may represent a novel therapeutic target or diagnostic biomarker for patients with HCC.