Cai Mingbo, Jin Shan, Deng Lu, Zhu Liancheng, Hu Zhenhua, Liu Dawo, Liu Juanjuan, Tan Mingzi, Gao Jian, Wang Huimin, Lin Bei
Department of Obstetrics and Gynecology, Shengjing Hospital Affiliated to China Medical University, Heping District, Shenyang 110004, Liaoning, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhongyuan District, Zhengzhou 450000, Henan, China.
Oncotarget. 2017 Nov 8;8(66):110064-110076. doi: 10.18632/oncotarget.22617. eCollection 2017 Dec 15.
As a tumor-associated carbohydrate antigen, elevated expression of Lewis y promotes the malignant behaviors of tumor cells. Although our preliminary study showed that the increased expression of Lewis y antigen decreased the expression of cell cycle inhibitor protein p27, the relevant mechanism remains unclear. Autophagy and the ubiquitin-proteasome system are two main ways of intracellular protein degradation, whose abnormal activities are closely associated with progression of malignant tumors. In our present study, we constructed two stable transfected cell lines with high expression of Lewis y antigen, named CAOV3-FUT1 and SKOV3-FUT1. We showed that the proportion of cells at S phase was significantly increased after FUT1 transfection, whereas p27 protein was obviously decreased. The autophagy activity, the levels of ubiquitination, and chymotrypsin-like protease activity were increased remarkably in the transfected cells. Interestingly, Lewis y antigen promoted the degradation of p27 by increasing ubiquitin-proteasome activity. In the vivo studies, Lewis y antigen improved the tumorigenic ability of ovarian cancer cells in nude mice and reduced the expression of p27. These findings suggested that Lewis y antigen activated both the autophagy and ubiquitin-proteasome activity and promoted the degradation of p27 through the ubiquitin-proteasome pathway.
作为一种肿瘤相关碳水化合物抗原，Lewis y的高表达促进肿瘤细胞的恶性行为。尽管我们的初步研究表明Lewis y抗原表达增加会降低细胞周期抑制蛋白p27的表达，但其相关机制仍不清楚。自噬和泛素 - 蛋白酶体系统是细胞内蛋白质降解的两种主要方式，其异常活动与恶性肿瘤的进展密切相关。在本研究中，我们构建了两个Lewis y抗原高表达的稳定转染细胞系，命名为CAOV3 - FUT1和SKOV3 - FUT1。我们发现FUT1转染后S期细胞比例显著增加，而p27蛋白明显减少。转染细胞中的自噬活性以及泛素化水平和类胰凝乳蛋白酶活性显著增加。有趣的是，Lewis y抗原通过增加泛素 - 蛋白酶体活性促进p27的降解。在体内研究中，Lewis y抗原提高了卵巢癌细胞在裸鼠中的致瘤能力并降低了p27的表达。这些发现表明Lewis y抗原激活了自噬和泛素 - 蛋白酶体活性，并通过泛素 - 蛋白酶体途径促进p27的降解。
