{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,19]],"date-time":"2025-12-19T09:30:07Z","timestamp":1766136607847,"version":"3.41.2"},"reference-count":46,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,1,1]]},"abstract":"<jats:p>Hypoxia inducible factor 1\u03b1 (HIF1\u03b1) is a transcription factor that regulates adaptation of cells to hypoxic microenvironments, for example inside solid tumors. Stabilization of HIF1\u03b1 can also occur in normoxic conditions in inflamed tissue or as a result of inactivating mutations in negative regulators of HIF1\u03b1. Aberrant overexpression of HIF1\u03b1 in many different cancers has led to intensive efforts to develop HIF1\u03b1 targeted therapies. However, the role of HIF1\u03b1 is still poorly understood in chronic inflammation that predisposes the colon to carcinogenesis. We have previously reported that Hif1\u03b1 transcription is upregulated and the protein is stabilised in inflammatory lesions which are caused by the non-steroidal anti-inflammatory drug (NSAID) sulindac in the mouse proximal colon. Here we exploited this side effect of long-term sulindac administration to analyse the role of Hif1\u03b1 in colon inflammation using mice with a Villin cre-induced deletion of Hif1\u03b1 exon 2 in the intestinal epithelium (Hif1\u03b1\u0394IEC ). We also analysed the effect of sulindac sulfide on the Aryl Hydrocarbon Receptor (AHR) pathway in vitro in colon cancer cells. Most sulindac-treated mice developed visible lesions, resembling the appearance of flat or depressed adenomas in the human colon, surrounded by macroscopically normal mucosa. Hif1\u03b1\u0394IEC mice still developed lesions but they were smaller than in the Hif1\u03b1-floxed siblings (Hif1\u03b1F\/F). Microscopically, Hif1\u03b1\u0394IEC mice had significantly less severe colon inflammation than Hif1\u03b1F\/F mice. Molecular analysis showed reduced MIF and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1\u03b1\u0394IEC mice. However, immunohistochemistry analysis revealed a defect of E-cadherin protein expression in sulindac-treated Hif1\u03b1\u0394IEC mice. Sulindac sulfide treatment in vitro upregulated Hif1\u03b1, c-JUN and IL8 expression through the AHR pathway. Taken together, Hif1\u03b1 expression augments inflammation in the proximal colon of sulindac-treated mice and AHR activation by sulindac may lead to the reduction of E-cadherin protein levels through the MAPK pathway.<\/jats:p>","DOI":"10.1242\/dmm.019000","type":"journal-article","created":{"date-parts":[[2015,7,17]],"date-time":"2015-07-17T00:50:17Z","timestamp":1437094217000},"source":"Crossref","is-referenced-by-count":10,"title":["HIF1\u03b1 deficiency reduces colon inflammation in a mouse model of proximal colon cancer"],"prefix":"10.1242","author":[{"given":"Dessislava N.","family":"Mladenova","sequence":"first","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane E.","family":"Dahlstrom","sequence":"additional","affiliation":[{"name":"ACT Pathology, The Canberra Hospital and Australian National University Medical School, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Phuong N.","family":"Tran","sequence":"additional","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fahad","family":"Benthani","sequence":"additional","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine G.","family":"Bean","sequence":"additional","affiliation":[{"name":"ACT Pathology, The Canberra Hospital and Australian National University Medical School, Canberra, ACT, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irvin","family":"Ng","sequence":"additional","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Pangon","sequence":"additional","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Currey","sequence":"additional","affiliation":[{"name":"Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maija R. 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