| First Author | Triner D | Year | 2017 |
| Journal | Mol Cell Biol | Volume | 37 |
| Issue | 5 | PubMed ID | 27956697 |
| Mgi Jnum | J:244844 | Mgi Id | MGI:5913623 |
| Doi | 10.1128/MCB.00481-16 | Citation | Triner D, et al. (2017) Epithelial Hypoxia-Inducible Factor 2alpha Facilitates the Progression of Colon Tumors through Recruiting Neutrophils. Mol Cell Biol 37(5) |
| abstractText | 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-2alpha in colon tumors; however, the function of epithelial HIF-2alpha as a critical link in the progression of inflammation to cancer has not been elucidated. In colitis-associated colon cancer models, epithelial HIF-2alpha was essential in tumor growth. Concurrently, epithelial disruption of HIF-2alpha significantly decreased neutrophils in the colon tumor microenvironment. Intestinal epithelial HIF-2alpha-overexpressing mice demonstrated that neutrophil recruitment was a direct response to increased epithelial HIF-2alpha signaling. High-throughput RNA sequencing (RNA-seq) analysis of HIF-2alpha-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-2alpha-dependent manner. Using selective peptide inhibitors of the CXCL1-CXCR2 signaling axis identified HIF-2alpha-dependent neutrophil recruitment as an essential mechanism to increase colon carcinogenesis. These studies demonstrate that HIF-2alpha is a novel regulator of neutrophil recruitment to colon tumors and that it is essential in shaping the protumorigenic inflammatory microenvironment in colon cancer. |
