title: Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils.
abstract: Inflammation is a significant risk factor for colon cancer. Recent work has demonstrated essential roles for several infiltrating immune populations in the metaplastic progression following inflammation. Hypoxia and stabilization of hypoxia-inducible factors (HIFs) are hallmark features of inflammation and solid tumors. Previously, we demonstrated an important role for tumor epithelial HIF-2α in colon tumors; however, the function of epithelial HIF-2α as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2α was essential in tumor growth. Concurrently, epithelial disruption of HIF-2α significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2α-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2α signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2α-overexpressing mice in conjunction with data mining from the Cancer Genome Atlas showed that the neutrophil chemokine CXCL1 gene was highly upregulated in colon tumor epithelium in a HIF-2α-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2α-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2α is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Triner
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Schwartz
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Inkyung
authors.initials: I
authors.lastname: Jung
authors.affiliation: Department of Environmental Health Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.|Department of Nutritional Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Colacino
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA shahy@umich.edu.|Department of Internal Medicine, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D002633:Chemotaxis; D003092:Colitis / Q000150:complications / Q000473:pathology; D003110:Colonic Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D054360:Chemokine CXCL1; D004268:DNA-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C076035:c-MYC-associated zinc finger protein
keywords: HIF-2α; cancer; colon; colon cancer; hypoxia; inflammation; neutrophils