MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX

Cell Signal. 2014 Feb;26(2):179-85. doi: 10.1016/j.cellsig.2013.11.003. Epub 2013 Nov 9.

Abstract

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 1 (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.

Keywords: 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide; Apoptosis-related molecule; BMP; Cell survival; EMT; Gemcitabine; HSP; ID; IPMN; Inhibitor of DNA binding; MTT; Mitochondrial protein; SHC1; Src Homology 2 Domain Containing 1; bone morphogenetic protein; epithelial–mesenchymal transition; heat shock protein; intraductal papillary mucinous neoplasm.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxycytidine / analogs & derivatives
  • Deoxycytidine / chemistry
  • Deoxycytidine / pharmacology
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • bcl-2-Associated X Protein / genetics
  • bcl-2-Associated X Protein / metabolism*

Substances

  • 3' Untranslated Regions
  • MIRN365 microRNA, human
  • MicroRNAs
  • RNA, Small Interfering
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • bcl-2-Associated X Protein
  • Deoxycytidine
  • gemcitabine