Journal article
The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis
PLoS genetics, Vol.9(12), pp.e1003937-e1003937
2013
DOI: 10.1371/journal.pgen.1003937
PMCID: PMC3868529
PMID: 24367269
Abstract
Viral hepatitis, obesity, and alcoholism all represent major risk factors for hepatocellular carcinoma (HCC). Although these conditions also lead to integrated stress response (ISR) or unfolded protein response (UPR) activation, the extent to which these stress pathways influence the pathogenesis of HCC has not been tested. Here we provide multiple lines of evidence demonstrating that the ISR-regulated transcription factor CHOP promotes liver cancer. We show that CHOP expression is up-regulated in liver tumors in human HCC and two mouse models thereof. Chop-null mice are resistant to chemical hepatocarcinogenesis, and these mice exhibit attenuation of both apoptosis and cellular proliferation. Chop-null mice are also resistant to fibrosis, which is a key risk factor for HCC. Global gene expression profiling suggests that deletion of CHOP reduces the levels of basal inflammatory signaling in the liver. Our results are consistent with a model whereby CHOP contributes to hepatic carcinogenesis by promoting inflammation, fibrosis, cell death, and compensatory proliferation. They implicate CHOP as a common contributing factor in the development of HCC in a variety of chronic liver diseases.
Details
- Title: Subtitle
- The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis
- Creators
- Diane DeZwaan-McCabe - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaJesse D Riordan - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaAngela M Arensdorf - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaMichael S Icardi - Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaAdam J Dupuy - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of AmericaD Thomas Rutkowski - Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America ; Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America
- Resource Type
- Journal article
- Publication Details
- PLoS genetics, Vol.9(12), pp.e1003937-e1003937
- DOI
- 10.1371/journal.pgen.1003937
- PMID
- 24367269
- PMCID
- PMC3868529
- NLM abbreviation
- PLoS Genet
- ISSN
- 1553-7390
- eISSN
- 1553-7404
- Publisher
- Public Library Science; United States
- Grant note
- R01 DK084058 / NIDDK NIH HHS R01 CA132962 / NCI NIH HHS
- Language
- English
- Date published
- 2013
- Academic Unit
- Anatomy and Cell Biology; Pathology; Internal Medicine
- Record Identifier
- 9984025370702771
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