RNF220 enhances USP22 to promote cell growth, metastasis and stemness in hepatocellular carcinoma by activating the Akt pathway.

Hepatocellular carcinoma (HCC) is characterized by high metastatic potential and poor prognosis. Ring finger protein 220 (RNF220) has been implicated in tumorigenesis across various cancers; however, its role and associated regulatory mechanisms in HCC remain unclear. In this study, analysis of The Cancer Genome Atlas (TCGA) database revealed that RNF220 expression was significantly elevated in liver hepatocellular carcinoma (LIHC) tissues and was associated with poor prognosis. Further experiments confirmed the upregulation of RNF220 mRNA and protein in HCC tissues. Functional assays demonstrated that RNF220 overexpression promoted cell proliferation, migration and stemness, whereas RNF220 knockdown suppressed these processes in HCC cells. Mechanistically, RNF220 enhanced ubiquitin-specific protease 22 (USP22) expression, leading to activation of the protein kinase B (Akt) pathway. Furthermore, the knockdown of RNF220 inhibited HCC progression, an effect that could be reversed by SC79 (an Akt activator), an Akt activator. In vivo experiments further confirmed that RNF220 aggravated tumor growth and metastasis. In summary, these findings indicate that RNF220 promotes HCC progression by regulating USP22 and activating the Akt pathway, suggesting that RNF220 may serve as a potential biomarker and therapeutic target for HCC.