Colorectal cancer (CRC) is one of the leading causes of cancer related mortality in the developed countries. Interestingly, the host laboratory has recently discovered that the homeobox transcription factor PROX1 is overexpressed in the vast majority of human CRCs as well as in mouse models of intestinal cancer with abnormal beta-catenin/TCF signaling. Furthermore, they provided evidence that PROX1 is regulated by the high concentration of beta-catenin and this regulation seems to be tissue specific. As PROX1 expression was found to be specifically associated with the transition from benign to malignant tumor phenotype and in normal colonic and small intestinal epithelium PROX1 expression is restricted only to some enteroendocrine cells, targeting PROX1 seems to be a novel possibility for anti-CRC drugs. The aim of this proposal is to develop an endodermal cell model for the analysis of PROX1 function in the intestine by using induced pluripotent stem cells, furthermore, to identify inhibitors that regulate PROX1 activity or kill PROX1+ cells in CRC and to validate their effect. To achieve the aims, dominant negative constructs will be generated, the direct target genes of PROX1 will be determined by combining expression and ChIP-on-Chip microarray data, high-throughput chemical library screening will be carried out and the effect of candidates will be validated by using different in vitro and in vivo systems.
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