title: The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis.
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.
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Diane
authors.initials: D
authors.lastname: DeZwaan-McCabe
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Riordan
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Arensdorf
authors.affiliation: Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Icardi
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa Carver College of Medicine, Iowa City, Iowa, United States of America.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.affiliation: 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.
authors.forename: D Thomas
authors.initials: DT
authors.lastname: Rutkowski
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D051379:Mice; D013312:Stress, Physiological / Q000235:genetics; D051742:Transcription Factor CHOP / Q000096:biosynthesis* / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics
chemical_list: C497249:DDIT3 protein, human; D051742:Transcription Factor CHOP