MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX
MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX
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DOI：
10.1016/j.cellsig.2013.11.003
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发表时间：
2014-02-01
影响因子：
4.8
通讯作者：
Shimosegawa, Tooru
中科院分区：
文献类型：
--
作者：
Hamada, Shin;Masamune, Atsushi;Shimosegawa, Tooru
胰腺浸润性导管腺癌预后不良主要是由于其对治疗药物的耐药性。发病率提高细胞存活的分子机制已被广泛研究，但在治疗策略上尚未取得根本的改进。最近的报道表明，miRNA通过全面靶向基因簇在多种细胞功能中发挥重要作用。我们在之前的研究中发现了几个在浸润性导管腺癌中高表达的mirna，并阐明了它们在上皮-间质转化中的作用。在差异表达的mirna中，miR-365在浸润性导管腺癌中高表达，其功能作用尚未报道。在目前的研究中，我们发现miR-365诱导胰腺癌细胞对吉西他滨耐药。MiR-365直接靶向适配器蛋白Src Homology 2 Domain Containing I （SHC1）和促凋亡蛋白BAX。基于sirna的SHC1和BAX的敲低增加了吉西他滨耐药性，表明miR-365/SHC1/BAX轴影响胰腺癌细胞的存活。此外，miR-365上调DNA结合抑制剂2、S100P等促癌分子，提示其与其他促癌信号存在串扰。MiR-365可能对胰腺癌细胞的存活发挥协同作用。(C) 2013爱思唯尔公司版权所有。
The poor prognosis of invasive ductal adenocarcinoma of the pancreas is mainly due to its resistance against therapeutic agents. The molecular mechanism by which morbidity enhances cell survival has been extensively studied, but radical improvements in the therapeutic strategy have not yet been achieved. Recent reports have indicated the substantial contribution of miRNA in multiple cell functions by comprehensively targeting clusters of genes. We identified several miRNAs highly expressed in invasive ductal adenocarcinoma in our previous study, and clarified their contribution to the epithelial-mesenchymal transition. Among the differentially expressed miRNAs, miR-365 was highly expressed in invasive ductal adenocarcinoma, whose functional role has not been reported. In the current study, we found that miR-365 induced gemcitabine resistance in pancreatic cancer cells. MiR-365 directly targeted adaptor protein Src Homology 2 Domain Containing I (SHC1) and apoptosis-promoting protein BAX. The siRNA-based knockdown of SHC1 and BAX increased gemcitabine resistance, indicating the miR-365/SHC1/BAX axis influences the survival of pancreatic cancer cells. In addition, miR-365 up-regulated cancer-promoting molecules such as Inhibitor of DNA binding 2 and S100P, suggesting the existence of cross-talk with other cancer-promoting signals. MiR-365 could exert orchestrated effects on pancreatic cancer cell survival. (C) 2013 Elsevier Inc. All rights reserved.