miR-320c regulates gemcitabine-resistance in pancreatic cancer via SMARCC1

Br J Cancer. 2013 Jul 23;109(2):502-11. doi: 10.1038/bjc.2013.320. Epub 2013 Jun 25.

Abstract

Background: Gemcitabine-based chemotherapy is the standard treatment for pancreatic cancer. However, the issue of resistance remains unresolved. The aim of this study was to identify microRNAs (miRNAs) that govern the resistance to gemcitabine in pancreatic cancer.

Methods: miRNA microarray analysis using gemcitabine-resistant clones of MiaPaCa2 (MiaPaCa2-RGs), PSN1 (PSN1-RGs), and their parental cells (MiaPaCa2-P, PSN1-P) was conducted. Changes in the anti-cancer effects of gemcitabine were studied after gain/loss-of-function analysis of the candidate miRNA. Further assessment of the putative target gene was performed in vitro and in 66 pancreatic cancer clinical samples.

Results: miR-320c expression was significantly higher in MiaPaCa2-RGs and PSN1-RGs than in their parental cells. miR-320c induced resistance to gemcitabine in MiaPaCa2. Further experiments showed that miR-320c-related resistance to gemcitabine was mediated through SMARCC1, a core subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex. In addition, clinical examination revealed that only SMARCC1-positive patients benefited from gemcitabine therapy with regard to survival after recurrence (P=0.0463).

Conclusion: The results indicate that miR-320c regulates the resistance of pancreatic cancer cells to gemcitabine through SMARCC1, suggesting that miR-320c/SMARCC1 could be suitable for prediction of the clinical response and potential therapeutic target in pancreatic cancer patients on gemcitabine-based therapy.

MeSH terms

  • Aged
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Carcinoma, Pancreatic Ductal / drug therapy
  • Carcinoma, Pancreatic Ductal / genetics*
  • Carcinoma, Pancreatic Ductal / mortality
  • Carcinoma, Pancreatic Ductal / surgery
  • Cell Line, Tumor
  • Cell Survival / genetics
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / physiology
  • Humans
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / physiology*
  • Middle Aged
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / surgery
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transfection

Substances

  • Antimetabolites, Antineoplastic
  • MIRN320 microRNA, human
  • MicroRNAs
  • SMARCC1 protein, human
  • Transcription Factors
  • Deoxycytidine
  • gemcitabine