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Epithelial Hypoxia-Inducible Factor 2? 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-2? in colon tumors; however, the function of epithelial HIF-2? as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2? was essential in tumor growth. Concurrently, epithelial disruption of HIF-2? significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2?-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2? signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2?-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-2?-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2?-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2? is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer.

SUBMITTER: Triner D

PROVIDER: S-EPMC5311236 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils.

Triner Daniel D Xue Xiang X Schwartz Andrew J AJ Jung Inkyung I Colacino Justin A JA Shah Yatrik M YM

Molecular and cellular biology 20170215 5

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 inf ...[more]

PMID: 27956697

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Project description:Hypoxia is a notable feature of inflammatory bowel disease and chronic induction of hypoxia-inducible factor (HIF)-1α and HIF-2α (endothelial PAS domain protein 1, EPAS1) play important, but opposing, roles in its pathogenesis. While activation of HIF-1α decreases intestinal inflammation and is beneficial in colitis, activation of HIF-2α exacerbates colitis and increases colon carcinogenesis in animal models, primarily due to the role of epithelial HIF-2α in mounting a potent inflammatory response. Previous work from our laboratory showed that mice overexpressing intestinal epithelial HIF-2α led to massive intestinal inflammation and decreased survival. As oxygen homeostasis and HIFs are critical in embryonic development, it is not clear whether the observed intestinal inflammatory response was secondary to developmental defects. To address this question, the present study used a mouse model to temporally modulate expression of intestinal epithelial HIF-2α to assess its role in mediating inflammatory response. Remarkably, activation of HIF-2α in intestinal epithelial cells in adult mice increased expression of proinflammatory mediators; however, no decrease in survival was observed. Furthermore, in an acute model of colitis, activation of HIF-2α was sufficient to exacerbate colitis. These data confirm our previous finding that epithelial HIF-2α mediates inflammatory response and demonstrates that activation of HIF-2α is sufficient to exacerbate colitis.NEW & NOTEWORTHY Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestinal tract. Hypoxia and activation of its downstream transcription factors hypoxia-inducible factor (HIF)-1α and HIF-2α are notable features of IBD. HIF-1α has well-characterized protective roles in IBD; however, the role of HIF-2α has been less studied. Using novel HIF-2α mouse models, we show that activation of HIF-2α in intestinal epithelial cells is sufficient to exacerbate colitis.

Dataset Information

Epithelial Hypoxia-Inducible Factor 2? Facilitates the Progression of Colon Tumors through Recruiting Neutrophils.

Publications

Epithelial Hypoxia-Inducible Factor 2α Facilitates the Progression of Colon Tumors through Recruiting Neutrophils.

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