Bernaudo S, Salem M, Qi X, Zhou W, Zhang C, Yang W, Rosman D, Deng Z, Ye G, Yang B B, Vanderhyden B, Wu Z, Peng C
Department of Biology, York University, Toronto, Ontario, Canada.
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
Oncogene. 2016 Sep 8;35(36):4816-27. doi: 10.1038/onc.2016.15. Epub 2016 Feb 15.
Epithelial ovarian cancer (EOC) has the highest mortality rate among gynecological malignancies owing to poor screening methods, non-specific symptoms and limited knowledge of the cellular targets that contribute to the disease. Cyclin G2 is an unconventional cyclin that acts to oppose cell cycle progression. Dysregulation of the cyclin G2 gene (CCNG2) in a variety of human cancers has been reported; however, the role of cyclin G2 in tumorigenesis remains unclear. In this study, we investigated the function of cyclin G2 in EOC. In vitro and in vivo studies using several EOC-derived tumor cell lines revealed that cyclin G2 inhibited cell proliferation, migration, invasion and spheroid formation, as well as tumor formation and invasion. By interrogating cDNA microarray data sets, we found that CCGN2 mRNA is reduced in several large cohorts of human ovarian carcinoma when compared with normal ovarian surface epithelium or borderline tumors of the ovary. Mechanistically, cyclin G2 was found to suppress epithelial-to-mesenchymal transition (EMT), as demonstrated by the differential regulation of various EMT genes, such as Snail, Slug, vimentin and E-cadherin. Moreover, cyclin G2 potently suppressed the Wnt/β-catenin signaling pathway by downregulating key Wnt components, namely LRP6, DVL2 and β-catenin, which could be linked to inhibition of EMT. Taken together, our novel findings demonstrate that cyclin G2 has potent tumor-suppressive effects in EOCs by inhibiting EMT through attenuating Wnt/β-catenin signaling.
上皮性卵巢癌（EOC）在妇科恶性肿瘤中死亡率最高，原因是筛查方法欠佳、症状不具特异性以及对导致该疾病的细胞靶点了解有限。细胞周期蛋白G2是一种非常规细胞周期蛋白，其作用是阻碍细胞周期进程。已有报道称细胞周期蛋白G2基因（CCNG2）在多种人类癌症中存在失调；然而，细胞周期蛋白G2在肿瘤发生中的作用仍不清楚。在本研究中，我们调查了细胞周期蛋白G2在EOC中的功能。使用几种源自EOC的肿瘤细胞系进行的体外和体内研究表明，细胞周期蛋白G2抑制细胞增殖、迁移、侵袭和球体形成，以及肿瘤形成和侵袭。通过分析cDNA微阵列数据集，我们发现与正常卵巢表面上皮或卵巢交界性肿瘤相比，在几个人类卵巢癌大样本队列中CCGN2 mRNA水平降低。从机制上讲，细胞周期蛋白G2被发现可抑制上皮-间质转化（EMT），各种EMT基因（如Snail、Slug、波形蛋白和E-钙黏蛋白）的差异调节证明了这一点。此外，细胞周期蛋白G2通过下调关键的Wnt成分，即低密度脂蛋白受体相关蛋白6（LRP6）、Dishevelled蛋白2（DVL2）和β-连环蛋白，有力地抑制了Wnt/β-连环蛋白信号通路，这可能与EMT的抑制有关。综上所述，我们的新发现表明，细胞周期蛋白G2通过减弱Wnt/β-连环蛋白信号通路抑制EMT，从而在EOC中具有强大的肿瘤抑制作用。
