MicroRNA-34a Alleviates Gemcitabine Resistance in Pancreatic Cancer by Repression of Cancer Stem Cell Renewal
MicroRNA-34a Alleviates Gemcitabine Resistance in Pancreatic Cancer by Repression of Cancer Stem Cell Renewal
复制标题
MicroRNA-34a 通过抑制癌症干细胞更新来减轻胰腺癌中的吉西他滨耐药性
DOI：
10.1097/mpa.0000000000001920
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发表时间：
2021-10-01
期刊：
影响因子：
2.9
通讯作者：
Xiao, Gary Guishan
中科院分区：
文献类型：
--
作者：
Pan, Yue;Li, Kun;Xiao, Gary Guishan
目的探讨microRNA-34 a（miR-34 a）介导的Notch 1靶向性对胰腺导管腺癌细胞的敏感性。方法采用MTT法（3-（4，5）-dimethylthiahiazo（-2）-3，5-diphenyltetrazoliumromide）测定细胞活力。采用定量聚合酶链反应测定miR-34 a及相关mRNA的表达水平。蛋白质水平通过蛋白质印迹法测量。通过细胞侵袭性和球体形成测定来评估细胞干性。建立移植瘤模型进行体内实验。结果MicroRNA-34 a在体内外均能增强吉西他滨的敏感性。microRNA-34 a抑制胰腺癌干细胞的干细胞性和增殖。MicroRNA-34 a与Notch 1直接相关，Notch 1位于上皮-间充质转化信号通路的上游。结论miR-34 a可通过抑制胰腺癌干细胞中Notch 1信号通路而使胰腺癌细胞对吉西他滨敏感，提示miR-34 a有望成为治疗吉西他滨耐药胰腺导管腺癌细胞的新药物。
Objectives This study aimed to enhance the sensitivity of pancreatic ductal adenocarcinoma cells by microRNA-34a (miR-34a)-mediated targeting of Notch 1. Methods Cell viability was determined by using an MTT (3-(4,5)-dimethylthiahiazo(-2)-3,5-diphenytetrazoliumromide) assay. The expression levels of miR-34a and relevant mRNAs were determined using quantitative polymerase chain reaction. Protein levels were measured by Western blotting. Cellular stemness was assessed by cell invasiveness and sphere formation assays. A transplanted tumor model was established for in vivo experiments. Results MicroRNA-34a enhanced gemcitabine sensitivity both in vivo and in vitro. MicroRNA-34a suppressed the stemness and proliferation of pancreatic cancer stem cells. MicroRNA-34a directly associated with Notch 1, which lies upstream of epithelial-mesenchymal transition signaling pathways. Conclusions MicroRNA-34a sensitized pancreatic cancer cells to gemcitabine treatment by inhibiting Notch 1 signaling in pancreatic cancer stem cells, indicating that miR-34a has the potential to be developed as a novel therapeutic agent for the treatment of gemcitabine-resistant pancreatic ductal adenocarcinoma cells.