Objective 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. Fields of science social sciencessociologydemographymortalitymedical and health sciencesmedical biotechnologycells technologiesstem cellsmedical and health sciencesclinical medicineoncologycolorectal cancer Keywords Anticancer therapy ChIP-on-Chip Genomics Molecular biology PROX1 chemical library screening induced pluripotent stem cell microarray Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Topic(s) FP7-PEOPLE-IEF-2008 - Marie Curie Action: "Intra-European Fellowships for Career Development" Call for proposal FP7-PEOPLE-IEF-2008 See other projects for this call Funding Scheme MC-IEF - Intra-European Fellowships (IEF) Coordinator HELSINGIN YLIOPISTO EU contribution € 184 759,18 Address YLIOPISTONKATU 3 00014 Helsingin Yliopisto Finland See on map Region Manner-Suomi Helsinki-Uusimaa Helsinki-Uusimaa Activity type Higher or Secondary Education Establishments Administrative Contact Katariina Vainio-Mattila (Ms.) Links Contact the organisation Opens in new window Website Opens in new window Total cost No data
