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 hypoxiainducible 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.KEYWORDS HIF-2␣, inflammation, colon cancer, cancer, colon, hypoxia, neutrophils C olon cancer remains a significant public health concern and is the second leading cause of cancer-associated deaths in the United States (1). Patients with chronic inflammation associated with inflammatory bowel disease (IBD), comprising ulcerative colitis and Crohn's disease, are at an increased lifetime risk of developing colon cancer; these tumors are termed colitis-associated cancers (CAC) (2). The genetic changes of sporadic colon cancer have been well defined, and a comprehensive genetic analysis of CAC was recently reported (3). In contrast to sporadic colon cancer, CAC are associated with early loss of the TP53 tumor suppressor and less frequent inactivation of adenomatous polyposis coli (APC) (4). Inflammation is an important component of the progression of sporadic cancer, and the inflammatory response is essential in the initiation and progression of CAC (5). The precise mechanisms that initiate the protumorigenic response following inflammation remain unknown.Hypoxia is a characteristic feature of IBD and nearly all solid tumors, including those of the colon (6). Hypoxia promotes activation of the hypoxia-inducible factors (HIFs). HIFs consist of a heterodimer of an O 2 -labile ␣-subunit (HIF-1␣, HIF-2␣, and HIF-3␣) and an O 2 -stable ␤-subunit (ARNT) (7). HIFs regulate transcription of target genes that mediate cellular responses to hypoxic microenvironments. HIFs are also essenti...

Myc-Associated Zinc Finger Protein Regulates the Proinflammatory Response in Colitis and Colon Cancer via STAT3 Signaling

“…Furthermore, MAZ was shown to have cell-autonomous regulation of cell growth in colon cancer cells both in vitro and in vivo. Recently, our work suggested an important role for MAZ in the inflammatory progression of colon cancer by regulating HIF-2␣-mediated expression of the potent neutrophil chemokine gene Cxcl1 (10). In the present study, we have discovered a novel HIF-2␣-independent function for MAZ in the regulation of STAT3 signaling.…”

“…MAZ splice variants 1 and 3 are activated by inflammation, whereas MAZ2 is anti-inflammatory (8,9). Our previous work has identified an essential role for MAZ in hypoxia-driven inflammatory responses in both colitis and colon cancer (10). MAZ is a direct protein interactor of hypoxia-inducible transcription factor 2␣ (HIF-2␣) and is important for HIF-2␣ transactivation of inflammatory target genes such as the tumor necrosis factor ␣ gene (Tnfa) (11,12).…”

Hypoxia inducible factor-2α increases sensitivity of colon cancer cells towards oxidative cell death

“…and DMF. We have previously shown that HIF-2α is a critical transcription factor involved in colon cancer progression 46 . Our drug screen data on enteroids from a hypoxic colon cancer mouse identifies erastin, RSL3, sorafenib and DMF as major molecules that could significantly reduce the growth of these hypoxic cells.…”

The interplay between neutrophils and microbiota in cancer

“…Tumor size and level of hypoxia can also establish the extent or type of neutrophil recruitment. Hypoxia‐inducible factor (HIF)‐2α expression in epithelial cells leads to colon tumor formation and expression of CXCL1 . In the KRAS/p53 genetic model of lung carcinogenesis, large tumors contain more neutrophils than small tumors.…”

“…Hypoxia-inducible factor (HIF)-2 expression in epithelial cells leads to colon tumor formation and expression of CXCL1. 102 In the KRAS/p53 genetic model of lung carcinogenesis, 103 large tumors contain more neutrophils than small tumors. This ability of larger, more hypoxic tumor to attract neutrophils is due to HIF-1 -induced Snail, which induces Cxcl2 expression in both the tumors and neutrophils.…”