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Invasion and metastasis are the main cause of recurrence and death in advanced hepatocellular carcinoma (HCC). Revealing the mechanisms of HCC metastasis is important for developing new therapeutic approaches and reducing patient mortality. Ubiquitin specific protease 4 (USP4), is involved in tumorigenesis by deubiquitinating some important oncogenic proteins and impacting their degradation. In the present study, we found that USP4 was significantly upregulated in HCC tumor tissues and the high expression of USP4 was associated with distant metastasis and poor survival in patients. Using gene interference, we demonstrated that USP4 knockdown significantly inhibited HCC cell migration and invasion in vitro, and USP4 overexpression had the opposite results. In vivo, we also found that USP4 knockdown obviously blocked HCC cell metastasis. Mechanistically, we revealed that USP4 interacted directly with and deubiquitinated TGF-β receptor type I (TGFR-1) to activate the TGF-β signaling pathway, and subsequently induced the Epithelial-Mesenchymal Transition (EMT) in HCC cells. Taken together, our results elucidate that USP4 is highly expressed in HCC and promotes the tumor invasion and metastasis, the underlying mechanism is that USP4 directly interacts with and deubiquitinates TGFR-1 to increase TGF-β signaling-Induced EMT. These results could provide a new therapeutic target for the treatment of HCC.

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