PPARD and Interferon Gamma Promote Transformation of Gastric Progenitor Cells and Tumorigenesis in Mice.


Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
07 2019
Historique:
received: 05 09 2018
revised: 20 02 2019
accepted: 12 03 2019
pubmed: 20 3 2019
medline: 31 7 2019
entrez: 20 3 2019
Statut: ppublish

Résumé

The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer. We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays. Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis. We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.

Sections du résumé

BACKGROUND & AIMS
The peroxisome proliferator-activated receptor delta (PPARD) regulates cell metabolism, proliferation, and inflammation and has been associated with gastric and other cancers. Villin-positive epithelial cells are a small population of quiescent gastric progenitor cells. We expressed PPARD from a villin promoter to investigate the role of these cells and PPARD in development of gastric cancer.
METHODS
We analyzed gastric tissues from mice that express the Ppard (PPARD1 and PPARD2 mice) from a villin promoter, and mice that did not carry this transgene (controls), by histology and immunohistochemistry. We performed cell lineage-tracing experiments and analyzed the microbiomes, chemokine and cytokine production, and immune cells and transcriptomes of stomachs of these mice. We also performed immunohistochemical analysis of PPARD levels in 2 sets of human gastric tissue microarrays.
RESULTS
Thirty-eight percent of PPARD mice developed spontaneous, invasive gastric adenocarcinomas, with severe chronic inflammation. Levels of PPARD were increased in human gastric cancer tissues, compared with nontumor tissues, and associated with gastric cancer stage and grade. We found an inverse correlation between level of PPARD in tumor tissue and patient survival time. Gastric microbiomes from PPARD and control mice did not differ significantly. Lineage-tracing experiments identified villin-expressing gastric progenitor cells (VGPCs) as the origin of gastric tumors in PPARD mice. In these mice, PPARD up-regulated CCL20 and CXCL1, which increased infiltration of the gastric mucosa by immune cells. Immune cell production of inflammatory cytokines promoted chronic gastric inflammation and expansion and transformation of VGPCs, leading to tumorigenesis. We identified a positive-feedback loop between PPARD and interferon gamma signaling that sustained gastric inflammation to induce VGPC transformation and gastric carcinogenesis.
CONCLUSIONS
We found PPARD overexpression in VPGCs to result in inflammation, dysplasia, and tumor formation. PPARD and VGPCs might be therapeutic targets for stomach cancer.

Identifiants

pubmed: 30885780
pii: S0016-5085(19)33572-3
doi: 10.1053/j.gastro.2019.03.018
pmc: PMC6581611
mid: NIHMS1524109
pii:
doi:

Substances chimiques

CCL20 protein, mouse 0
Chemokine CCL20 0
Chemokine CXCL1 0
Chemokines 0
Cxcl1 protein, mouse 0
Cytokines 0
Microfilament Proteins 0
Ppard protein, mouse 0
Receptors, Cytoplasmic and Nuclear 0
Vil1 protein, mouse 0
Interferon-gamma 82115-62-6

Types de publication

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

Langues

eng

Pagination

163-178

Subventions

Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206539
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA195686
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK056338
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA142969
Pays : United States

Informations de copyright

Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Auteurs

Xiangsheng Zuo (X)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: xzuo@mdanderson.org.

Yasunori Deguchi (Y)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Weiguo Xu (W)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Yi Liu (Y)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Haiyan S Li (HS)

Departments of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Daoyan Wei (D)

Departments of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Rui Tian (R)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Weidong Chen (W)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Min Xu (M)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Yaying Yang (Y)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Shen Gao (S)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Jonathan C Jaoude (JC)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Fuyao Liu (F)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Sarah P Chrieki (SP)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Micheline J Moussalli (MJ)

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Mihai Gagea (M)

Departments of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Manu M Sebastian (MM)

Departments of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Xiaofeng Zheng (X)

Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Dongfeng Tan (D)

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Russell Broaddus (R)

Departments of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Jing Wang (J)

Departments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Nadim J Ajami (NJ)

Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas.

Alton G Swennes (AG)

Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas; Center for Comparative Medicine, Baylor College of Medicine, Houston, Texas.

Stephanie S Watowich (SS)

Departments of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Imad Shureiqi (I)

Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: ishureiqi@mdanderson.org.

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