HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties
- University of Michigan, United States
- New York University, United States
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 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 pancreatic ductal adenocarcinoma.
Data availability
All data from this study is available without limitations (GSE108151).
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HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem CellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE108151).
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Cancer Genome AtlasNo restrictions; all data available without limitations.
Article and author information
Author details
Funding
Gershenson Pancreatic Cancer Fund
- Diane M Simeone
SKY Foundation
- Howard C Crawford
- Diane M Simeone
American Cancer Society (127662-PF-15-033-01-DDC)
- Ethan V Abel
Pancreatic Cancer Action Network (16-70-25-ABEL)
- Ethan V Abel
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Richard M White, Memorial Sloan Kettering Cancer Center, United States
Ethics
Animal experimentation: All animal protocols were approved by University Committee for the Use and Care of Animals (UCUCA) at The University of Michigan. The animal welfare assurance number for this study is A3114-01. Every effort was made throughout this study to minimize stress to and suffering of animal subjects.
Human subjects: Patient samples were collected under a protocol approved by the IRB at the The University of Michigan. All patients gave informed consent. The human assurance number for this study is FWA00004969.
Version history
- Received: November 29, 2017
- Accepted: August 1, 2018
- Accepted Manuscript published: August 3, 2018 (version 1)
- Version of Record published: September 4, 2018 (version 2)
Copyright
© 2018, Abel et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties
eLife 7:e33947.
https://doi.org/10.7554/eLife.33947
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