HBV-associated hepatocellular carcinoma (HCC) represents the prevalent form of HCC, with HBx protein being a crucial oncoprotein. Numerous members of the protein tyrosine phosphatase nonreceptor (PTPN) family have been confirmed to be significantly associated with the occurrence and progression of malignant tumors. Our group previously identified the involvement of PTPN13 in HCC. However, the roles of other PTPNs in HCC require further investigation. In this study, we found that PTPN18 expression was significantly downregulated within HCC tissues compared with adjacent nontumor and reference liver tissues. Functionally, PTPN18 exerted inhibitory effects on the proliferation, migration, invasion, and sphere-forming capability of HCC cells while concurrently promoting apoptotic processes. Through phospho-protein microarray screening followed by subsequent validation experiments, we identified that PTPN18 could activate the p53 signaling pathway and suppress the AKT/FOXO1 signaling cascade in HCC cells. Moreover, the HBx protein mediated the repression of PTPN18 expression by upregulating miR-128-3p. Collectively, our study unveiled the role of PTPN18 as a tumor suppressor in HBV-related HCC.

Implications: Our findings revealed that PTPN18 might be a potential diagnostic and therapeutic target for HBV-related HCC.

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