Deregulation of the MiR-193b-KRAS Axis Contributes to Impaired Cell Growth in Pancreatic Cancer

PLoS One. 2015 Apr 23;10(4):e0125515. doi: 10.1371/journal.pone.0125515. eCollection 2015.

Abstract

Modulation of KRAS activity by upstream signals has revealed a promising new approach for pancreatic cancer therapy; however, it is not clear whether microRNA-associated KRAS axis is involved in the carcinogenesis of pancreatic cancer. Here, we identified miR-193b as a tumor-suppressive miRNA in pancreatic ductal adenocarcinoma (PDAC). Expression analyses revealed that miR-193b was downregulated in (10/11) PDAC specimens and cell lines. Moreover, we found that miR-193b functioned as a cell-cycle brake in PDAC cells by inducing G1-phase arrest and reducing the fraction of cells in S phase, thereby leading to dampened cell proliferation. miR-193b also modulated the malignant transformation phenotype of PDAC cells by suppressing anchorage-independent growth. Mechanistically, KRAS was verified as a direct effector of miR-193b, through which the AKT and ERK pathways were modulated and cell growth of PDAC cells was suppressed. Taken together, our findings indicate that miR-193b-mediated deregulation of the KRAS axis is involved in pancreatic carcinogenesis, and suggest that miR-193b could be a potentially effective target for PDAC therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology*
  • Cell Line, Tumor
  • Cell Proliferation
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Signal Transduction

Substances

  • 3' Untranslated Regions
  • KRAS protein, human
  • MIRN193 microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins p21(ras)

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 81172334 and 30471970) (URL: http://www.nsfc.gov.cn/), and the National Key Technology R&D program (No. 2006BAI02A14) (URL:http://www.most.gov.cn/index.htm). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.