1. Systems Biology Division and Propriumbio Research Center, Zhejiang-California International Nanosystems Institute (ZCNI), Zhejiang University, Hangzhou, Zhejiang Prov., China; ; 2. Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
J Cancer. 2013 Sep 27;4(8):662-70. doi: 10.7150/jca.6641. eCollection 2013.
Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH-terminal ubiquityl esters and amides. It has been reported as either an oncogene or a tumor suppressor in cancers. However, UCHL1's role in ovarian cancer is still unclear. Therefore, we conducted an analysis to understand the role of UCHL1 in ovarian cancer. Firstly, we detected UCHL1 promoter methylation status in 7 ovarian cancer cell lines. 4 of them with UCHL1 silencing showed heavy promoter methylation while the other 3 with relative high UCHL1 expression showed little promoter methylation. Then we reduced UCHL1 expression in ovarian cancer cell line A2780 and IGROV1 and found that inhibition of UCHL1 promoted cell proliferation by increasing cells in S phases of cell cycle. Knockdown of UCHL1 also reduced cell apoptosis and contributed to cisplatin resistance. Furthermore, the expression level of UCHL1 in several ovarian cancer cell lines correlated negatively with their cisplatin resistance levels. Microarray data revealed that UCHL1 related genes are enriched in apoptosis and cell death gene ontology (GO) terms. Several apoptosis related genes were increased after UCHL1 knockdown, including apoptosis regulator BCL2, BCL11A, AEN and XIAP. Furthermore, we identified up-regulation of Bcl-2 and pAKT as well as down-regulation of Bax in UCHL1 knockdown cells, while no significant alteration of p53 and AKT1 was found. This study provides a new and promising strategy to overcome cisplatin resistance in ovarian cancer via UCHL1 mediated pathways.
泛素羧基末端水解酶 1（UCHL1）催化 COOH 末端泛素酯和酰胺的水解。它在癌症中被报道为癌基因或肿瘤抑制因子。然而，UCHL1 在卵巢癌中的作用仍不清楚。因此，我们进行了一项分析，以了解 UCHL1 在卵巢癌中的作用。首先，我们检测了 7 种卵巢癌细胞系中 UCHL1 启动子的甲基化状态。其中 4 种 UCHL1 沉默的细胞系表现出强烈的启动子甲基化，而另外 3 种相对高表达 UCHL1 的细胞系表现出很少的启动子甲基化。然后，我们在卵巢癌细胞系 A2780 和 IGROV1 中降低了 UCHL1 的表达，发现抑制 UCHL1 通过增加细胞周期 S 期的细胞来促进细胞增殖。UCHL1 的敲低也减少了细胞凋亡，并有助于顺铂耐药。此外，几种卵巢癌细胞系中 UCHL1 的表达水平与它们的顺铂耐药水平呈负相关。微阵列数据显示，UCHL1 相关基因富集在凋亡和细胞死亡的基因本体（GO）术语中。UCHL1 敲低后，包括凋亡调节因子 BCL2、BCL11A、AEN 和 XIAP 在内的几个凋亡相关基因上调。此外，我们发现 UCHL1 敲低细胞中 Bcl-2 和 pAKT 的上调以及 Bax 的下调，而 p53 和 AKT1 没有明显变化。这项研究为通过 UCHL1 介导的途径克服卵巢癌顺铂耐药提供了一个新的、有前途的策略。
