Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma
Bortezomib Stabilizes Mitotic Cyclins and Prevents Cell Cycle Progression via Inhibition of UBE2C in Colorectal Carcinoma
复制标题
DOI：
10.1016/j.ajpath.2011.01.034
复制
发表时间：
2011-05-01
影响因子：
6
通讯作者：
Al-Kuraya, Khawla S.
中科院分区：
文献类型：
--
作者：
Bavi, Prashant;Uddin, Shahab;Al-Kuraya, Khawla S.
大量证据表明，泛素偶联酶E2C （UBE2C）基因在包括结直肠癌（CRC）在内的几种人类癌症中起作用。因此，我们研究了CRC中UBE2C改变和CRC细胞系中UBE2C信号传导的预后价值。应用免疫组织化学和TMA荧光原位杂交技术检测临床样品UBE2C蛋白表达和UBE2C基因拷贝数。通过凋亡实验和免疫印迹法评估蛋白酶体抑制剂硼替佐米和小干扰RNA敲除的作用。UBE2C失调与增殖标志物Ki-67、细胞周期蛋白A和B1的积累以及较差的总生存率相关。UBE2C表达是早期（I和II） CRC的独立预后指标。UBE2C缺失导致细胞生长和细胞周期蛋白A和B1的积累受到抑制。在体外，硼替佐米处理CRC细胞通过下调UBE2C抑制细胞活力。硼替佐米抑制UBE2C或转染针对UBE2C的特异性小干扰RNA也会导致细胞在G2/M水平阻滞，导致细胞周期蛋白A和细胞周期蛋白B1的积累。在体内，与单独使用奥沙利铂或硼替佐米治疗相比，使用亚毒性剂量奥沙利铂和硼替佐米联合治疗的小鼠肿瘤体积和重量显著减少。总之，我们的研究结果表明，UBE2C和泛素-蛋白酶体途径可能是CRC治疗干预的潜在靶点。（中华病理学杂志，2011,178:2109-2120;DOI: 10.1016/ j.j ajpath.2011.01.034）
Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of sub-toxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC. (AmJ Pathol 2011, 178: 2109-2120; DOI: 10.1016/j.ajpath.2011.01.034)