Department of Colorectal Surgery, The Affiliated 3rd Hospital, Harbin Medical University, Harbin, China.
Cell Biochem Biophys. 2012 Jan;62(1):229-35. doi: 10.1007/s12013-011-9287-0.
Recent studies provided strong support for the view that ubiquitin-specific protease 22 (USP22) plays a central role in cell-cycle progression and also in pathological processes such as oncogenesis. We have recently shown that USP22 levels are elevated in colorectal carcinoma with associated increase in the expression of several cell-cycle-related genes. However, the precise mechanism for these functions of USP22 at molecular level has not been fully elucidated. Currently, we investigated the role of USP22 in human colorectal cancer (CRC). We observed that USP22 expression was statistically significantly correlated positively with that of BMI-1, c-Myc and both, pAkt (Ser473), and pAkt (Thr308), in primary tumor tissues from 43 CRC patients. Down-regulation of USP22 expression in HCT116 colorectal cancer cells by siRNA resulted in the accumulation of cells in the G1 phase of the cell cycle. RNAi-knockdown of USP22 in HCT16 cells also led to the repression of BMI-1 and was accompanied by the up-regulation of p16INK4a and p14ARF, with a consequent decrease in E2F1 and p53 levels. In addition, down-regulation of c-Myc-targeted cyclin D2 was also noticed in cells treated with USP22-siRNA. Furthermore, our results showed that USP22 deletion also caused down-regulation of Akt/GSK3β activity, which can also contribute to the reduction of cyclin D2. Collectively, our current results suggest that USP22 may act as an oncogene in CRC as it positively regulates cell cycle via both BMI-1-mediated INK4a/ARF pathway and Akt signaling pathway.
最近的研究为泛素特异性蛋白酶 22（USP22）在细胞周期进程中发挥核心作用以及在肿瘤发生等病理过程中发挥作用提供了有力支持。我们最近表明，USP22 水平在结直肠癌中升高，伴随着几个细胞周期相关基因的表达增加。然而，USP22 在分子水平上的这些功能的精确机制尚未完全阐明。目前，我们研究了 USP22 在人结直肠癌（CRC）中的作用。我们观察到，在 43 名 CRC 患者的原发性肿瘤组织中，USP22 的表达与 BMI-1、c-Myc 和两者的 pAkt（Ser473）和 pAkt（Thr308）的表达呈正相关。在 HCT116 结直肠癌细胞中通过 siRNA 下调 USP22 表达导致细胞在细胞周期的 G1 期积累。HCT16 细胞中 USP22 的 RNAi 敲低也导致 BMI-1 的抑制，并伴随着 p16INK4a 和 p14ARF 的上调，从而导致 E2F1 和 p53 水平降低。此外，还注意到用 USP22-siRNA 处理的细胞中 c-Myc 靶向的细胞周期蛋白 D2 的下调。此外，我们的结果表明，USP22 的缺失也导致 Akt/GSK3β 活性的下调，这也有助于细胞周期蛋白 D2 的减少。总之，我们目前的结果表明，USP22 可能作为 CRC 的癌基因发挥作用，因为它通过 BMI-1 介导的 INK4a/ARF 途径和 Akt 信号通路正向调节细胞周期。
