miR-34a 通过抑制肿瘤干细胞更新缓解胰腺癌对吉西他滨的耐药性
MicroRNA-34a Alleviates Gemcitabine Resistance in Pancreatic Cancer by Repression of Cancer Stem Cell Renewal.
机构信息
From the State Key Laboratory of Fine Chemicals, Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian.
Department of Laboratory Medicine, The Third Xiangya Hospital, Central South University, Changsha, China.
出版信息
Pancreas. 2021 Oct 1;50(9):1260-1266. doi: 10.1097/MPA.0000000000001920.
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.
目的
本研究旨在通过 microRNA-34a（miR-34a）靶向 Notch 1 来提高胰腺导管腺癌细胞的敏感性。
方法
通过 MTT（3-(4,5)-二甲基噻唑 (-2)-3,5-二苯基四氮唑溴盐）测定法测定细胞活力。使用定量聚合酶链反应测定 miR-34a 和相关 mRNA 的表达水平。通过 Western blot 测定蛋白水平。通过细胞侵袭和球体形成测定评估细胞干性。建立了用于体内实验的移植瘤模型。
结果
miR-34a 体内和体外均增强了吉西他滨的敏感性。miR-34a 抑制了胰腺肿瘤干细胞的干性和增殖。miR-34a 直接与 Notch 1 结合，而 Notch 1 位于上皮-间充质转化信号通路的上游。
结论
miR-34a 通过抑制胰腺肿瘤干细胞中的 Notch 1 信号来增强胰腺癌细胞对吉西他滨的敏感性，表明 miR-34a 有可能被开发为治疗吉西他滨耐药的胰腺导管腺癌细胞的新型治疗剂。
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