CONICET | Buscador de Institutos y Recursos Humanos

CFTR mutations cause not only cystic fibrosis disease, but also increase the risk of colorectal cancer. However, its probably role in colorectal cancer from patients without cystic fibrosis has not been previously investigated. RAC3 is a nuclear receptor coactivator usually overexpressed in several tumors, required to maintaining the cancer stemness. We investigated the functional relationship between CFTR and RAC3 for maintaining cancer stemness in human colorectal cancer.Previously we investigated cancer stemness using a stable transfection of shCFTR or shRAC3 in HCT116 cells, and we found that CFTR downregulation inhibits the cancer stem phenotype. We alsofound that CD133+ side population expresses higher levels of RAC3 and CFTR than CD133- and RAC3 overexpression increases CFTR expression.To further investigate this, we performed bioinformatics analysis in both human colorectal cancer samples and Caco-2 cells. In order to do these we used two datasets: 1) CD133+ or CD133- side populations and 2) CFTRwt or CFTRmut cells. First we analyzed the expression levels of CFTR mRNA in colorectal cancer samples from patients without cystic fibrosis using the Xena platform (TCGA). The CFTR mRNA without mutations was higher than the CFTR mRNA with mutations and this correlates with an increased expression of RAC3. Then we compared the gene expression between CD133+ cells and CFTRwt cells using different platforms (ConsensusPathDB, STRING, Cytoscape, GeneMANIA). We found a common gene expression pattern between them involved in inflammatory and nuclear receptor pathways that contribute to colorectal cancer development.From these and our previous results we conclude that although CFTR mutation may increase the risk of colorectal cancer, there are other pathways by which CFTR overexpression may also contribute to this disease, maintaining the cancer stemness and inducing tumor development.