Department of Colorectal Surgery, the Affiliated Tumor Hospital, Harbin Medical University, Harbin, China.
J Gastroenterol Hepatol. 2010 Nov;25(11):1800-5. doi: 10.1111/j.1440-1746.2010.06352.x.
Increasing experimental evidence suggests that ubiquitin-specific protease 22 (USP22) could exhibit a critical function in pathological processes, including oncogenesis and cell cycle progression. The aim of this study was to investigate the role of USP22 and the association with its potential targets in colorectal cancer (CRC).
We evaluated the implication of USP22 and the candidate targets, such as B-cell-specific murine leukemia virus integration site-1 (BMI-1), cellular homolog of avian myelocytomatosis virus oncogene (c-Myc), cyclin D2, inhibitor of cyclin-dependent kinase (CDK) 4 (p16INK4a), and an alternate reading frame product of the CDKN2A locus (p14ARF), in matched samples comprising carcinoma and adjacent non-cancerous mucosa from 82 patients with CRC using quantitative reverse transcription-polymerase chain reaction and immunostaining analyses.
The USP22 mRNA expression in the CRC tissues was significantly higher than those in the non-cancerous mucosa tissues (P < 0.0001). Increased mRNA expression of USP22 was associated with advanced American Joint Committee on Cancer stage (P = 0.033) and high likelihood of therapy failure after radical resection (P < 0.0001). The Cox regression analysis revealed that the USP22 mRNA expression level was a significant factor for predicting prognosis (P < 0.0001). The statistical correlation analysis in mRNA levels showed that USP22 was strongly correlated with BMI-1 (r = 0.790, P < 0.0001), c-Myc (r = 0.528, P < 0.0001), and cyclin D2 (r = 0.657, P < 0.0001), but not p16INK4a (r = 0.103, P = 0.358) or p14ARF (r = -0.039, P = 0.731).
Our results indicate that activation of USP22 correlates with CRC progression and therapy failure. Additionally, the oncogenic role of USP22 in the progression of CRC can be mechanistically linked with BMI-1, c-Myc, and cyclin D2, but not with p16INK4a and p14ARF.
越来越多的实验证据表明，泛素特异性蛋白酶 22（USP22）在包括肿瘤发生和细胞周期进展在内的病理过程中可能发挥关键作用。本研究旨在探讨 USP22 的作用及其与潜在靶点的关联在结直肠癌（CRC）中的作用。
我们评估了 USP22 及其候选靶点（如 B 细胞特异性鼠白血病病毒整合位点 1（BMI-1）、禽髓细胞瘤病毒致癌基因的细胞同源物（c-Myc）、细胞周期蛋白 D2、细胞周期蛋白依赖性激酶 4（CDK4）抑制剂（p16INK4a）和 CDKN2A 基因座的交替读框产物（p14ARF））在 82 例 CRC 患者癌组织和癌旁非癌组织中的表达，采用定量逆转录聚合酶链反应和免疫组化分析。
CRC 组织中 USP22mRNA 的表达明显高于非癌组织（P<0.0001）。USP22mRNA 表达增加与美国癌症联合委员会（AJCC）晚期分期（P=0.033）和根治性切除后治疗失败的高可能性相关（P<0.0001）。Cox 回归分析显示，USP22mRNA 表达水平是预测预后的重要因素（P<0.0001）。mRNA 水平的统计学相关性分析显示，USP22 与 BMI-1（r=0.790，P<0.0001）、c-Myc（r=0.528，P<0.0001）和 cyclin D2（r=0.657，P<0.0001）呈强烈相关，但与 p16INK4a（r=0.103，P=0.358）或 p14ARF（r=-0.039，P=0.731）不相关。
我们的研究结果表明，USP22 的激活与 CRC 的进展和治疗失败相关。此外，USP22 在 CRC 进展中的致癌作用可能与其潜在靶点 BMI-1、c-Myc 和 cyclin D2 相关，而与 p16INK4a 和 p14ARF 无关。
