HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

Elife. 2018 Aug 3:7:e33947. doi: 10.7554/eLife.33947.

Abstract

The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a human PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, decreased PCSC marker expression, and downregulation of POU5F1/OCT4 expression. Conversely, HNF1A overexpression increased PCSC marker expression and tumorsphere formation in pancreatic cancer cells and drove pancreatic ductal adenocarcinoma (PDA) cell growth. Importantly, depletion of HNF1A in xenografts impaired tumor growth and depleted PCSC marker-positive cells in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of PCSC properties and novel oncogene in PDA.

Keywords: HNF1A; OCT4; POU5F1; cancer biology; human; pancreatic cancer stem cells; pancreatic ductal adenocarcinoma; patient survival; regenerative medicine; stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Humans
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Oncogenes / genetics
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / pathology
  • Xenograft Model Antitumor Assays

Substances

  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha