Zinc finger E-box-binding homeobox 2 (ZEB2) regulated by miR-200b contributes to multi-drug resistance of small cell lung cancer
Zinc finger E-box-binding homeobox 2 (ZEB2) regulated by miR-200b contributes to multi-drug resistance of small cell lung cancer
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miR-200b调控的锌指E盒结合同源盒2（ZEB2）有助于小细胞肺癌的多药耐药
DOI：
10.1016/j.yexmp.2014.04.008
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发表时间：
2014-06-01
影响因子：
3.6
通讯作者：
Guo, Linlang
中科院分区：
文献类型：
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作者：
Fang, Shun;Zeng, Xiangping;Guo, Linlang
锌指E盒结合同源框2(ZEB2)与肿瘤的发生、发展及化疗反应密切相关。然而，其在小细胞肺癌(SCLC)中的生物学功能仍不清楚。本研究旨在探讨ZEB2在小细胞肺癌化疗耐药中的作用及其可能的分子机制。采用免疫组织化学方法检测68例小细胞肺癌组织中ZEB2的表达。在小细胞肺癌多药耐药细胞(H69AR)中进行ZEB2基因敲除，以评估其对化疗耐药的影响。结果显示，23.5%(16/68)的小细胞肺癌组织中有ZEB2的表达。ZEB2的过表达与小细胞肺癌的病理分期差(Fisher‘s Exact检验P<；0.001)和生存期短(Kaplan-Meier法)有关。小干扰RNA抑制H69AR细胞中ZEB2的表达通过增加药物诱导的细胞凋亡率而使肿瘤细胞对化疗药物增敏，并伴有S期阻滞。在计算机分析中证明miR-200b与ZEB2 3‘-UTR之间存在互补结合部位，并确定miR-200b是ZEB2的潜在调节因子。我们发现miR-200b在耐药细胞中表达下调，并通过miRNA模拟增强细胞敏感性而促进miR-200b的表达。MiR-200b过表达导致ZEB2蛋白表达下调。荧光素酶报告基因分析表明，3‘UTRZEB2活性受miR-200b调控。我们的结果表明，ZEB2调节耐药，并受miR-200b的调节。所有这些发现为深入了解ZEB2信号转导机制提供了线索，ZEB2可能成为小细胞肺癌多药耐药的潜在靶点。(C)2014 Elsevier Inc.保留所有权利。
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. (C) 2014 Elsevier Inc. All rights reserved.