microRNA-101在非小细胞肺癌中通过调控EZH2表达而发挥肿瘤抑制功能
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摘要
目的：非小细胞肺癌是一种发病率高、死亡率高、和对放化疗不敏感的常见恶性肿瘤,急需寻找新的治疗方法改善其预后。EZH2基因被证实在包括非小细胞肺癌在内的多种恶性肿瘤中呈高表达,与肿瘤攻击性和预后不佳相关,然而我们对EZH2高表达的机制知之甚少。miRNA是一种单链非编码小分子RNA,通过转录后水平调控基因的表达,是近年肿瘤学领域的研究热点。本研究旨在阐明miR-101调节非小细胞肺癌中EZH2表达,并观察miR-101和EZH2对肺癌细胞生物学特性的影响,为非小细胞肺癌治疗提供新方法和新策略。
方法：应用实时定量PCR和免疫组化方法检测20对非小细胞肺癌组织及其癌旁正常肺组织中miR-101和EZH2蛋白的表达。应用荧光素酶报告基因系统验证EZH2是miR-101的靶基因。为了观察miR-101和EZH2对非小细胞肺癌细胞生物学行为的影响,在肺癌细胞转染miR-101 mimics或特异沉默EZH2的siRNA后,我们用CCK-8法检测细胞增殖、transwell穿膜小室检测细胞侵袭和流式细胞学annexin V/PI双染法检测紫杉醇诱导的细胞凋亡
结果：在非小细胞肺癌组织中,miR-101低表达和EZH2过表达显著相关。在非小细胞肺癌细胞系中,miR-101显著抑制包含野生型而非突变型EZH2-3'UTR质粒的荧光素酶活性和减少EZH2 mRNA和蛋白的表达。增强miR-101表达或沉默EZH2基因能抑制肺癌细胞增殖和侵袭,并能通过诱导Bim表达而促进紫杉醇诱导肺癌细胞凋亡
结论：miR-101通过负性调节EZH2表达而抑制非小细胞肺癌细胞增殖和侵袭并增强紫杉醇诱导细胞凋亡。增强miR-101表达或沉默EZH2基因的治疗策略有望使非小细胞肺癌患者受益。
Purpose:Overexpression of the enhancer of zeste homolog 2 (EZH2) protein has been found in broad range of cancer types, including non small cell lung cancer (NSCLC). However, the mechanisms by which EZH2 becomes over-expressed in NSCLC remain unclear. microRNAs (miRNAs) can regulate target gene expression through translational control. With the present study we investigated whether microRNA (miR-101) regulates EZH2 expression in NSCLC.
Methods:We evaluated the expression of miR-101 and EZH2 in 20 matched NSCLC and adjacent non-tumor lung tissues by qRT-PCR and Immunohistochemistry, respectively. Luciferase reporter assay was used to determine whether miR-101 directly targets EZH2. To assess the effect of miR-101 on NSCLC biological behavior, cell proliferation, invasion and response to chemotherapy were analyzed using NSCLC cells transfected with miR-101 mimics or transfected with specific siRNA to deplete EZH2 (siRNA-EZH2).
Results:Reduced expression of miR-101 is associated with overxpression of EZH2 in NSCLC tumor tissues. Transfection of miR-101 mimics significantly suppressed the activity of the luciferase reporter containing wild type but not mutant EZH2 3'-UTR and decreased EZH2 mRNA and protein levels in NSCLC cell lines. Furthermore, enforced expression of miR-101 or knockdown of EZH2 led to reduced NSCLC cell proliferation and invasion and sensitized cancer cells to paclitaxel (PTX)-mediated apoptosis through inducing expression of the pro-apoptotic protein Bim.
Conclusions:miR-101 inhibits cell proliferation and invasion and enhances PTX-induced apoptosis in NSCLC cells, at least in part, by directly repressing EZH2 expression. Therapeutic strategies to rescue miR-101 expression or slience EZH2 may be beneficial to patients with NSCLC in the future.
方法：应用实时定量PCR和免疫组化方法检测20对非小细胞肺癌组织及其癌旁正常肺组织中miR-101和EZH2蛋白的表达。应用荧光素酶报告基因系统验证EZH2是miR-101的靶基因。为了观察miR-101和EZH2对非小细胞肺癌细胞生物学行为的影响,在肺癌细胞转染miR-101 mimics或特异沉默EZH2的siRNA后,我们用CCK-8法检测细胞增殖、transwell穿膜小室检测细胞侵袭和流式细胞学annexin V/PI双染法检测紫杉醇诱导的细胞凋亡
结果：在非小细胞肺癌组织中,miR-101低表达和EZH2过表达显著相关。在非小细胞肺癌细胞系中,miR-101显著抑制包含野生型而非突变型EZH2-3'UTR质粒的荧光素酶活性和减少EZH2 mRNA和蛋白的表达。增强miR-101表达或沉默EZH2基因能抑制肺癌细胞增殖和侵袭,并能通过诱导Bim表达而促进紫杉醇诱导肺癌细胞凋亡
结论：miR-101通过负性调节EZH2表达而抑制非小细胞肺癌细胞增殖和侵袭并增强紫杉醇诱导细胞凋亡。增强miR-101表达或沉默EZH2基因的治疗策略有望使非小细胞肺癌患者受益。
Purpose:Overexpression of the enhancer of zeste homolog 2 (EZH2) protein has been found in broad range of cancer types, including non small cell lung cancer (NSCLC). However, the mechanisms by which EZH2 becomes over-expressed in NSCLC remain unclear. microRNAs (miRNAs) can regulate target gene expression through translational control. With the present study we investigated whether microRNA (miR-101) regulates EZH2 expression in NSCLC.
Methods:We evaluated the expression of miR-101 and EZH2 in 20 matched NSCLC and adjacent non-tumor lung tissues by qRT-PCR and Immunohistochemistry, respectively. Luciferase reporter assay was used to determine whether miR-101 directly targets EZH2. To assess the effect of miR-101 on NSCLC biological behavior, cell proliferation, invasion and response to chemotherapy were analyzed using NSCLC cells transfected with miR-101 mimics or transfected with specific siRNA to deplete EZH2 (siRNA-EZH2).
Results:Reduced expression of miR-101 is associated with overxpression of EZH2 in NSCLC tumor tissues. Transfection of miR-101 mimics significantly suppressed the activity of the luciferase reporter containing wild type but not mutant EZH2 3'-UTR and decreased EZH2 mRNA and protein levels in NSCLC cell lines. Furthermore, enforced expression of miR-101 or knockdown of EZH2 led to reduced NSCLC cell proliferation and invasion and sensitized cancer cells to paclitaxel (PTX)-mediated apoptosis through inducing expression of the pro-apoptotic protein Bim.
Conclusions:miR-101 inhibits cell proliferation and invasion and enhances PTX-induced apoptosis in NSCLC cells, at least in part, by directly repressing EZH2 expression. Therapeutic strategies to rescue miR-101 expression or slience EZH2 may be beneficial to patients with NSCLC in the future.
引文
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