Oncogenic potential of Cyclin Kinase Subunit-2 in cholangiocarcinoma
Oncogenic potential of Cyclin Kinase Subunit-2 in cholangiocarcinoma
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细胞周期蛋白激酶亚基 2 在胆管癌中的致癌潜力
DOI：
10.1111/liv.12014
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发表时间：
2013-01-01
影响因子：
6.7
通讯作者：
Zhang, Zhi-Ming
中科院分区：
文献类型：
--
作者：
Shen, Dong-Yan;Zhan, Yi-Hong;Zhang, Zhi-Ming
研究背景细胞周期蛋白激酶亚基2（Cyclin kinase subunit-2，Cks 2）是人类Cks家族成员之一，在减数分裂和有丝分裂的调控中发挥重要作用，其异常表达通常与肿瘤发生有关。然而，其确切的功能和分子机制尚不清楚。目的观察Cks 2在胆管癌中的表达，探讨其在胆管癌发生发展中的作用及可能机制。方法采用免疫组化和RT-PCR方法检测胆管癌组织中Cks 2的表达。采用MTT法、集落形成法、免疫荧光法、流式细胞术和Western blotting等方法，探讨Cks 2在胆管癌中的作用及其可能机制。结果胆管癌组织中Cks 2表达明显升高，其过表达与胆管癌组织分化程度、CA 19 -9水平及预后有关。Cks 2表达下调可抑制胆管癌细胞的体外增殖和集落形成，抑制胆管癌异种移植瘤的生长，特别是增强胆管癌细胞对化疗的敏感性。我们进一步发现Cks 2基因敲低可通过下调Cyclin A和Cyclin B1的表达，上调Bax的表达和激活，线粒体膜通透性增加和caspase-3的激活，使胆管癌细胞周期阻滞于G2/M期，从而促进胆管癌细胞凋亡。结论Cks 2可能是胆管癌患者的独立预后因子，并通过促进细胞周期进程和caspase介导的线粒体caspase依赖性凋亡在胆管癌的发生发展中发挥重要作用。
Background Cyclin kinase subunit-2 (Cks2), a member of the human Cks family, plays an important role in the regulation of meiosis and mitosis; and its abnormal expression is usually associated with carcinogenesis. However, its exact functions and molecular mechanisms remain unclear. Aims To observe Cks2 expression in cholangiocarcinoma and explore its role in the carcinogenesis of cholangiocarcinoma and possible mechanism. Methods Cks2 expression in cholangiocarcinoma was detected with immunostaining and RT-PCR. MTT, colony formation, immunofluorescence, flow cytometry and Western blotting were performed to explore the role of Cks2 in cholangiocarcinoma and possible mechanism. Results Cks2 was significantly elevated in cholangiocarcinoma tissues and its over-expression was associated with poor differentiation, CA19-9 and poor prognosis. Furthermore, Cks2 down-regulation inhibited cholangiocarcinoma cell proliferation and colony formation in vitro, and the growth of cholangiocarcinoma xenografts in animals; especially, enhanced the sensitivity of cholangiocarcinoma cells to chemotherapy. We further found that Cks2 knockdown induced cholangiocarcinoma cell cycle arrest in G2/M phase through down-regulation of Cyclin A and Cyclin B1 and Bax up-regulation and activation, mitochondrial membrane permeabilization and caspase-3 activation, which resulted in facilitating cholangiocarcinoma apoptosis. Conclusions These findings suggest that Cks2 may serve as an independent prognostic factor in patients with cholangiocarcinoma, and play an important role in the carcinogenesis of cholangiocarcinoma by facilitating cell cycle progression and Bax-mediated mitochondrial caspase-dependent apoptosis.