Dicer regulates differentiation and viability during mouse pancreatic cancer initiation

PLoS One. 2014 May 1;9(5):e95486. doi: 10.1371/journal.pone.0095486. eCollection 2014.

Abstract

miRNA levels are altered in pancreatic ductal adenocarcinoma (PDA), the most common and lethal pancreatic malignancy, and intact miRNA processing is essential for lineage specification during pancreatic development. However, the role of miRNA processing in PDA has not been explored. Here we study the role of miRNA biogenesis in PDA development by deleting the miRNA processing enzyme Dicer in a PDA mouse model driven by oncogenic Kras. We find that loss of Dicer accelerates Kras driven acinar dedifferentiation and acinar to ductal metaplasia (ADM), a process that has been shown to precede and promote the specification of PDA precursors. However, unconstrained ADM also displays high levels of apoptosis. Dicer loss does not accelerate development of Kras driven PDA precursors or PDA, but surprisingly, we observe that mouse PDA can develop without Dicer, although at the expense of proliferative capacity. Our data suggest that intact miRNA processing is involved in both constraining pro-tumorigenic changes in pancreatic differentiation as well as maintaining viability during PDA initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinar Cells / metabolism
  • Acinar Cells / pathology
  • Animals
  • Carcinoma in Situ / genetics
  • Carcinoma in Situ / pathology
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Differentiation / genetics
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Disease Models, Animal
  • Gene Deletion
  • Metaplasia
  • Mice
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / pathology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology*
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Ribonuclease III / genetics*

Substances

  • Ribonuclease III
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)