miR-451a促进胰腺癌细胞对吉西他滨的敏感性

miR-451a Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine

目的:探究miR-451a在胰腺癌吉西他滨耐药中的功能。方法:通过低浓度梯度递增法建立胰腺癌吉西他滨耐药细胞株,microRNA(miRNA)测序筛选耐药相关miRNA;细胞存活曲线、克隆形成实验及流式凋亡实验分析miR-451a对胰腺癌细胞耐药的影响;裸鼠成瘤实验检测在动物体内模型中miR-451a对胰腺癌吉西他滨耐药的调控作用;调取TCGA数据分析miR-451a表达水平与胰腺癌病人预后的相关性。结果:胰腺癌吉西他滨耐药细胞株中miR-451a表达水平明显下调;miR-451a过表达增加胰腺癌细胞对吉西他滨的敏感性,增强了吉西他滨抑制细胞增殖和诱导细胞凋亡的作用;miR-451a诱导了裸鼠皮下肿瘤对吉西他滨敏感;miR-451a低表达与胰腺癌患者不良预后相关。结论:miR-451a增强了胰腺癌细胞对吉西他滨的敏感性。

Objective: To investigate the role of miR-451a in gemcitabine resistance of pancreatic cancer. Methods: Gemcitabine-resistant cell line was established by exposing wild type cell line to gradually increasing dose of gemcitabine. miRNA sequencing was used to screen drug-resistance-related miRNAs. The cell viability assay, colony formation assay and apoptosis detection were utilized to analyze the effect of miR-451a on gemcitabine sensitivity of pancreatic cancer cells. The xenografts in nude mice were used to detect the regulation of gemcitabine resistance by miR-451a in vivo. The data from TCGA database was analyzed to reveal the correlation of miR- 451a level and prognosis of pancreatic cancer patients. Results: miR-451a was downregulated in gemcitabine-resis? tant cell line. Overexpression of miR-451a enhanced the sensitivity of pancreatic cancer cells to gemcitabine, inhibited cell proliferation and promoted cell apoptosis induced by gemcitabine. Same results were obtained in xenograft models. The database analysis confirmed that low level of miR-451a was correlated to poor prognosis of pancreat? ic cancer patients. Conclusion: miR-451a can enhance the sensitivity of pancreatic cancer cells to gemcitabine.