β‐Catenin/TCF4 Is Required for DDX17‐Induced Epithelial–Mesenchymal Transition and Metastasis in Hepatocellular Carcinoma

ABSTRACT The DEAD‐box RNA helicase 17 (DDX17) is strongly linked to the occurrence and development of specific human cancers, emphasizing its previously unrecognized biological roles in cancer progression and metastasis. However, the precise mechanisms by which DDX17 regulates liver cancer metastasis have not been thoroughly explored. In this study, increased DDX17 expression levels showed a robust association with the invasive potential of hepatocellular carcinoma (HCC) cells. Silencing DDX17 expression resulted in substantial reduction of HCC cell migration and invasion potentials, while DDX17 overexpression had the opposite effect. Silencing DDX17 also attenuated epithelial–mesenchymal transition (EMT) in HCC cells and significantly reduced metastatic lesions in an orthotopic HCC nude mouse model. Mechanistically, chromatin immunoprecipitation assays revealed that TCF4 physically interacts with the DDX17 promoter, activating its transcriptional expression. Immunoprecipitation results demonstrated that DDX17‐mediated nuclear input of β‐catenin is dependent on its helicase functional domain. Furthermore, we demonstrated that β‐catenin/TCF4 is essential for DDX17‐induced migration and invasion in HCC cells. Taken together, these findings emphasize the significance of DDX17 in the malignant progression and metastasis of HCC, revealing a novel mechanism involving the β‐catenin/TCF4/DDX17 pathway.