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肺腺癌吉非替尼获得性耐药相关microRNAs的筛选鉴定

ISSN号：1009-3419
期刊名称：《中国肺癌杂志》
时间：0
分类：R734.2[医药卫生—肿瘤;医药卫生—临床医学]
作者机构：[1]天津医科大学总医院天津市肺癌研究所,天津市肺癌转移与肿瘤微环境重点实验,天津300052
相关基金：国家自然科学基金重点项目（No.30430300）国家自然科学基金项目（No.81000950）; 国家“863”重大项目（No.2006AAO2A401）; 国家“973”重大项目（No.2010CB529405）; 天津市科技支撑计划重点项目（No.06YFSZSF05300）; 天津市创新体系建设项目（No.07SYSYSF05000 No.07SYSYJC27900）资助; 中瑞合作重大项目（No.09ZCZDSF04100）资助~~

关键词：肺肿瘤, microRNA, 吉非替尼, 获得性耐药, Lung neoplasms, microRNAs, Gefitinib, Aquired-resistance

中文摘要：

背景与目的肺腺癌吉非替尼获得性耐药严重影响了肺癌的治疗效果,microRNA在肺腺癌吉非替尼获得性耐药中的作用及其机制尚不清楚。本研究筛选与肺腺癌获得性吉非替尼耐药相关的microRNAs。方法以吉非替尼敏感肺癌细胞PC9与吉非替尼耐药肺癌细胞PC9/AB11为细胞模型,观察二者的形态学差异,流式细胞仪检测二者的细胞周期,计算它们的倍增时间,MTT法检测吉非替尼对两种细胞的IC50,应用microRNA芯片检测和筛选与吉非替尼耐药相关的microRNAs,并进行real-timePCR验证。结果 PC9细胞与PC9/AB11细胞形态差异明显,在细胞周期、倍增时间和吉非替尼对其的IC50上均具有统计学差异。microRNA芯片结果显示,与PC9相比,耐药肺癌细胞株PC9/AB11中有4个microRNAs表达水平明显上调,有9个microRNAs表达水平明显下调。经real-timePCR验证,microRNA-138在PC9/AB11中表达明显下调,与芯片结果一致。结论 PC9和PC9/AB11细胞株microRNA表达谱存在明显差异,初步筛选到了13个与肺腺癌吉非替尼耐药密切相关的microRNAs,为进一步深入研究microRNA在肺腺癌吉非替尼获得性耐药中的作用及其分子机制提供了实验依据和理论基础。

英文摘要：

Background and objective Acquired gefitinib-resistance was closely related to inefficiency of EGFR-TKI treatment in lung adenocarcinoma. However, it was not clear that how microRNAs influenced the acquired gefitinib-resistance in lung adenocarcinoma. The aim of this study is to screen and identify the microRNAs correlated with the acquired gefitinib -resistance in lung adenocarcinoma. Methods Morphological difference was observed in gefitinib-sensitive lung adenocarcinoma cell line PC9 cell line and gefitinib-resistance lung adenocarcinoma cell line PC9/AB11 cell line derived from PC9 cell line. Cell cycles and doubling time were detected by flow cytometry, IC50 of gefitinib was evaluated by MTT assay. The differential microRNAs related to acquired gefitinib-resistance were screened and identified by microRNA array and real-time PCR. Results There were obvious morphological differences between PC9 and PC9/AB11 cells. The doubling time, distribu-tion of cell cycle, and the IC50 between PC9 and PC9/AB11 were significantly different. In microarray analysis, compared with PC9 cell line, 4 up-regulated microRNAs were found in PC9/AB11 cells, 9 down-regulated microRNAs were found in PC9/AB11 cells. Real-time PCR revealed that miR-138 was significantly down-regulated in PC9/AB11 cells, accord with the micro-array. Conclusion MicroRNAs are involved in acquired Gefitinib-resistance of lung adenocarcinoma. Our data presented here to provide an experimental basis and theory thereunder for further study of effect and molecule mechanism underlying the acquired gefitinib-resistance of lung cancer.

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