Xiao Weifan, Ou Chao, Qin Jinlong, Xing Feng, Sun Yi, Li Zhi, Qiu Jin
Department of Gynaecology and Obstetrics, Shanghai Tenth People's Hospital of Tongji University Shanghai 200072, China.
Department of Clinical Laboratory, The Affiliated Tumor Hospital of Guangxi Medical University Nanning 530021, Guangxi Province, China.
Int J Clin Exp Pathol. 2014 Jul 15;7(8):4817-26. eCollection 2014.
DNA damage response and repair are carried out by certain proteins following damage by environmental clastogens, such as ionizing radiation and reactive oxygen species. It has been reported that many carcinomas that are characterized by resistance to chemotherapy and poor outcomes show dysfunction of these proteins. Chromobox homologue 8 (CBX8), a member of the polycomb group of proteins, has been identified as a factor that protects tumor cells from the detrimental effects of ionizing radiation (IR) or hydrogen peroxide (H2O2). In this study, we found that CBX8 was up-regulated in esophageal carcinoma tissues compared with adjacent non-cancerous tissues (P<0.01) and correlated with TNM stage in esophageal squamous cell carcinoma patients. Depletion of CBX8 decreased cell proliferation both in vitro and in vivo and increased the phosphorylation levels of p21, Wee1, and CHK1, which result in cyclin-dependent kinase inhibition and cell-cycle delay. CBX8 depletion also led to accumulation of spontaneous DNA damage and raised the sensitivity of tumor cells to IR or H2O2. We also found that the total level of CBX8 in the cells was increased after treating tumor cells with clastogens. In addition, our data showed that decreased CBX8 expression was accompanied by the reduction of EZH2 and EED, which have been reported to participate in DNA damage repair. Collectively, CBX8 might emerge as an oncogene for promoting the proliferation of tumor cells and raising the resistance of neoplasms to chemotherapy.
DNA损伤反应和修复由某些蛋白质在受到环境致断裂剂（如电离辐射和活性氧）损伤后进行。据报道，许多以化疗耐药和预后不良为特征的癌症显示出这些蛋白质的功能障碍。多梳蛋白家族成员之一的染色体框同源物8（CBX8）已被确定为一种保护肿瘤细胞免受电离辐射（IR）或过氧化氢（H2O2）有害影响的因子。在本研究中，我们发现与相邻非癌组织相比，CBX8在食管癌组织中上调（P<0.01），并且与食管鳞状细胞癌患者的TNM分期相关。CBX8的缺失在体外和体内均降低细胞增殖，并增加p21、Wee1和CHK1的磷酸化水平，这导致细胞周期蛋白依赖性激酶抑制和细胞周期延迟。CBX8的缺失还导致自发DNA损伤的积累，并提高肿瘤细胞对IR或H2O2的敏感性。我们还发现，用致断裂剂处理肿瘤细胞后，细胞中CBX8的总水平增加。此外，我们的数据表明，CBX8表达降低伴随着EZH2和EED的减少，据报道这两种蛋白参与DNA损伤修复。总体而言，CBX8可能作为一种癌基因出现，促进肿瘤细胞增殖并提高肿瘤对化疗的抗性。
