Liao Shan, Xiao Songshu, Chen Hongxiang, Zhang Manying, Chen Zhifang, Long Yuehua, Gao Lu, Zhu Guangchao, He Junyu, Peng Shuping, Xiong Wei, Zeng Zhaoyang, Li Zheng, Zhou Ming, Li Xiaoling, Ma Jian, Wu Minghua, Xiang Juanjuan, Li Guiyuan, Zhou Yanhong
The Key Laboratory of Carcinogenesis of the Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha, Hunan, China.
The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan, China.
Mol Carcinog. 2017 Oct;56(10):2245-2257. doi: 10.1002/mc.22677. Epub 2017 Jun 30.
Cervical cancer is one of the most common malignant tumors in women all over the world. The exact mechanism of occurrence and development of cervical cancer has not been fully elucidated. CD38 is a type II transmembrane glycoprotein, which was found to mediate diverse activities, including signal transduction, cell adhesion, and cyclic ADP-ribose synthesis. Here, we reported that CD38 promoted cell proliferation and inhibited cell apoptosis in cervical cancer cells by affecting the mitochondria functions. We established stable cervical cancer cell lines with CD38 over-expressed. CCK8 assay and colony formation assay indicated that CD38 promoted cervical cancer cell proliferation. Nude mouse tumorigenicity assay showed that CD38 significantly promotes tumor growth in vivo. CD38 also induced S phase accumulation in cell cycle analysis and suppressed cell apoptosis in cervical cancer cells. Meanwhile, flow cytometry analysis of mitochondria functions suggested that CD38 decreased intracellular Ca levels in cervical cancer cells and CD38 was involved in down-regulation of ROS levels and prevented mitochondrial apoptosis in cervical cancer cells. The percentage of cells with loss of mitochondrial membrane potential (Δψm) in CD38-overexpressed cervical cancer cells was less than control groups. Furthermore, we found an up-regulation of MDM2, cyclinA1, CDK4, cyclinD1, NF-kB P65, c-rel, and a downregulation of P53, P21, and P38 by Western blot analysis. These results indicated that CD38 enhanced the proliferation and inhibited the apoptosis of cervical cancer cells by affecting the mitochondria functions.
宫颈癌是全球女性中最常见的恶性肿瘤之一。宫颈癌发生和发展的确切机制尚未完全阐明。CD38是一种II型跨膜糖蛋白，被发现可介导多种活动，包括信号转导、细胞粘附和环ADP核糖合成。在此，我们报告CD38通过影响线粒体功能促进宫颈癌细胞增殖并抑制细胞凋亡。我们建立了CD38过表达的稳定宫颈癌细胞系。CCK8检测和集落形成检测表明CD38促进宫颈癌细胞增殖。裸鼠致瘤性检测显示CD38在体内显著促进肿瘤生长。细胞周期分析中CD38还诱导S期积累并抑制宫颈癌细胞凋亡。同时，线粒体功能的流式细胞术分析表明CD38降低宫颈癌细胞内的钙水平，且CD38参与下调ROS水平并防止宫颈癌细胞的线粒体凋亡。CD38过表达的宫颈癌细胞中线粒体膜电位（Δψm）丧失的细胞百分比低于对照组。此外，通过蛋白质印迹分析我们发现MDM2、细胞周期蛋白A1、细胞周期蛋白依赖性激酶4、细胞周期蛋白D1、核因子κB P65、c-rel上调，而P53、P21和P38下调。这些结果表明CD38通过影响线粒体功能增强宫颈癌细胞的增殖并抑制其凋亡。
