Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Exp Mol Pathol. 2014 Jun;96(3):438-44. doi: 10.1016/j.yexmp.2014.04.008. Epub 2014 Apr 22.
Zinc finger E-box-binding homeobox 2 (ZEB2) was closely related to the oncogenesis, development and response to chemotherapy of cancer. However, its biological functions in small cell lung cancer (SCLC) remain unknown. The aim of this study is to investigate the roles of ZEB2 in chemoresistance of SCLC and its possible molecular mechanism. Expression of ZEB2 was examined in sixty-eight cases of SCLC tissues by immunohistochemistry. Knockdown of ZEB2 was carried out in SCLC multidrug resistant cells (H69AR) to assess its influence on chemoresistance. The results showed that ZEB2 was expressed in 23.5% (16/68) of SCLC. Overexpression of ZEB2 was associated with the poor pathologic stage of SCLC (P < 0.001 by the Fisher's Exact Test) and the shorter survival time (by the Kaplan-Meier method). Inhibition of ZEB2 expression using small interfering RNA in H69AR cells sensitized cancer cells to chemotherapeutic drugs through increasing drug-induced cell apoptosis accompanied with S phase arrest. In silico analysis demonstrated that there are complementary binding sites between miR-200b and ZEB2 3'-UTR, and identified miR-200b as a potential regulator of ZEB2. We found that miR-200b was down-regulated in the resistant cells and enforced expression of miR-200b by miRNA mimics increased cell sensitivity. Overexpression of miR-200b led to the downregulation of ZEB2 at protein level. Luciferase reporter gene assay showed that 3'UTR ZEB2 activity was regulated by miR-200b. Our results suggest that ZEB2 modulates drug resistance and is regulated by miR-200b. All findings provide insight into the ZEB2 signaling mechanism and ZEB2 may be a potentially novel target for multi-drug resistance in SCLC.
锌指 E 盒结合同源盒 2（ZEB2）与癌症的发生、发展和对化疗的反应密切相关。然而，其在小细胞肺癌（SCLC）中的生物学功能尚不清楚。本研究旨在探讨 ZEB2 在 SCLC 化疗耐药中的作用及其可能的分子机制。采用免疫组织化学法检测 68 例 SCLC 组织中 ZEB2 的表达。在 SCLC 多药耐药细胞（H69AR）中敲低 ZEB2，评估其对化疗耐药性的影响。结果显示，ZEB2 在 23.5%（16/68）的 SCLC 中表达。ZEB2 的过表达与 SCLC 较差的病理分期（Fisher 确切检验，P < 0.001）和较短的生存时间（Kaplan-Meier 法）相关。在 H69AR 细胞中用小干扰 RNA 抑制 ZEB2 表达可通过增加药物诱导的细胞凋亡并伴有 S 期阻滞，使癌细胞对化疗药物敏感。计算机分析表明，miR-200b 和 ZEB2 3'-UTR 之间存在互补结合位点，并确定 miR-200b 是 ZEB2 的潜在调节因子。我们发现，miR-200b 在耐药细胞中下调，用 miRNA 模拟物增强表达 miR-200b 可增加细胞敏感性。miR-200b 的过表达导致 ZEB2 蛋白水平下调。荧光素酶报告基因检测显示，3'-UTR ZEB2 活性受 miR-200b 调节。我们的结果表明，ZEB2 调节药物耐药性，并受 miR-200b 调节。所有发现都深入了解了 ZEB2 信号机制，ZEB2 可能是 SCLC 多药耐药的潜在新靶点。
