Knock-down of ubiquitin-specific protease 22 by micro-RNA interference inhibits colorectal cancer growth
Knock-down of ubiquitin-specific protease 22 by micro-RNA interference inhibits colorectal cancer growth
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DOI：
10.1007/s00384-011-1275-8
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发表时间：
2012-01-01
影响因子：
2.8
通讯作者：
Dong, Xin-Shu
中科院分区：
文献类型：
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作者：
Xu, Hui;Liu, Yan-Long;Dong, Xin-Shu
目的越来越多的实验证据表明，泛素特异性蛋白水解酶22(USP22)是一种肿瘤干细胞标记物，在上皮性恶性肿瘤等实体瘤的病理过程中发挥着重要作用，成为肿瘤治疗的潜在靶点。本研究旨在通过微干扰RNA(MiRNA)抑制USP22的表达，探讨USP22在人结肠癌细胞株HCT116中的作用。方法通过下调USP22的表达，观察USP22对人结肠癌细胞株HCT116细胞增殖、细胞周期、细胞凋亡及主要拱顶蛋白(MVP)表达的影响。结果miRNA下调USP22蛋白的表达，抑制细胞增殖，使细胞聚集于G1期，减少细胞凋亡，下调MVP的表达。此外，以原位小鼠为模型，注射USP22 miRNA沉默载体可抑制肿瘤生长。肿瘤切片的免疫组织化学分析显示，当miRNA抑制USP22的表达时，动物体内USP22的表达减少。结论这些结果支持了USP22通过USP22依赖的信号通路调节细胞增殖而在肿瘤的形成和生长中发挥重要作用的假说。此外，USP22是调控MVP耐药基因的主要转录因子。总而言之，靶向USP22可能在癌症治疗中提供更多的可能性。
Purpose 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).Methods 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.Results 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.Conclusion 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.