Publications

Abstract

Hypoxia-inducible factor 1alpha (HIF1alpha) is a transcription factor that regulates the adaptation of cells to hypoxic microenvironments, for example inside solid tumours. Stabilisation of HIF1alpha can also occur in normoxic conditions in inflamed tissue or as a result of inactivating mutations in negative regulators of HIF1alpha. Aberrant overexpression of HIF1alpha in many different cancers has led to intensive efforts to develop HIF1alpha-targeted therapies. However, the role of HIF1alpha is still poorly understood in chronic inflammation that predisposes the colon to carcinogenesis. We have previously reported that the transcription of HIF1alpha is upregulated and that the protein is stabilised in inflammatory lesions that 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 HIF1alpha in colon inflammation using mice with a Villin-Cre-induced deletion of Hif1alpha exon 2 in the intestinal epithelium (Hif1alpha(DeltaIEC)). 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 adenomas in the human colon, surrounded by macroscopically normal mucosa. Hif1alpha(DeltaIEC) mice still developed lesions but they were smaller than in the Hif1alpha-floxed siblings (Hif1alpha(F/F)). Microscopically, Hif1alpha(DeltaIEC) mice had significantly less severe colon inflammation than Hif1alpha(F/F) mice. Molecular analysis showed reduced MIF expression and increased E-cadherin mRNA expression in the colon of sulindac-treated Hif1alpha(DeltaIEC) mice. However, immunohistochemistry analysis revealed a defect of E-cadherin protein expression in sulindac-treated Hif1alpha(DeltaIEC) mice. Sulindac sulfide treatment in vitro upregulated Hif1alpha, c-JUN and IL8 expression through the AHR pathway. Taken together, HIF1alpha expression augments inflammation in the proximal colon of sulindac-treated mice, and AHR activation by sulindac might lead to the reduction of E-cadherin protein levels through the mitogen-activated protein kinase (MAPK) pathway.