Knock-down of ubiquitin-specific protease 22 by micro-RNA interference inhibits colorectal cancer growth

Abstract

Increasing experimental evidences suggest that ubiquitin-specific protease 22 (USP22), a cancer stem cell marker, plays a crucial role in pathological processes of epithelial malignancies and other solid tumors, which makes it a potential target for cancer therapy. The aim of this study was to study the roles of USP22 in human colorectal cancer cell line HCT116 by suppressing USP22 expression with micro-interfering RNA (miRNA). With the knock-down of USP22, the changes of cellular proliferation, cell cycle, cell apoptosis, and major vault protein (MVP) expression were investigated. Furthermore, a tumor xenograft model in nude mice was injected with USP22 miRNA silencing vector and the immunohistochemical staining was performed to evaluate the USP22 expression in the tumor. The knock-down of USP22 protein expression by miRNA resulted in the inhibition of cellular proliferation, the accumulation of cells in the G1 phase, the reduction of apoptosis, and the down-regulation of MVP expression. Furthermore, with orthotopic mice as a model, tumor growth was suppressed when USP22 miRNA silencing vector was injected. Immunohistochemical analyses of tumor sections revealed that USP22 expression in animals decreased when USP22 expression was inhibited by miRNA. These results support the hypothesis that USP22 plays a crucial role in tumor formation and growth by regulating cell proliferation with USP22-dependent signaling pathway. Furthermore, USP22 acts as a major transcriptional factor to regulate MVP drug resistant gene. Taken together, targeting USP22 may offer additional possibilities in cancer therapy.