The CFTR chloride channel regulates EGFR ligands expression

MARÍA MACARENA MASSIP COPIZ; ANGEL GABRIEL VALDIVIESO; CONSUELO MORI; MARIÁNGELES CLAUZURE; TOMÁS A. SANTA COLOMA

Mar del Plata

Congreso; LXI Reunión Anual de la Sociedad Argentina de Investigación Clínica; 2016

Cystic fibrosis (CF) is a rare autosomal recessive disease,caused by mutations in the cystic fibrosis transmembrane conductanceregulator (CFTR) gene. CFTR is a cAMP-activated chloridechannel, member of the superfamily of ABC (ATP Binding Cassette)transporter proteins. CFTR appears to function not only asa regulated chloride channel; it also acts as a signalling moleculeregulating different genes. Previously, we found that several geneshad altered expression due to the CFTR failure, such as SRC (atyrosine-kinase which in turn regulated MUC1), MTND4 (a mitochondrialgene encoding a subunit of the mitochondrial ComplexI), and CISD1 (a mitochondrial protein encoded in the nucleuswith a yet ill-defined function). Hence, the aim of the present workwas to determine if a failure in the CFTR activity (or expression)determines a differential regulation in the EGF receptor and itsligands. We use a cellular model consisting of Caco-2 cells (humancolon carcinoma epithelial cells) expressing wt-CFTR that werepreviously selected and cloned after transfections with short hairpinRNA interference (shRNA) directed against different regionsof CFTR (CaCo-2/pRS26) or with its control plasmid (CaCo-2/pRSctrl). The results obtained suggested that CFTR modulatessignificantly the expression of TGF-alpha, epiregulin and amphiregulinbut not the EGFR expression. As we observed an importantregulation of epiregulin ligand by CFTR, we continue to study thepossible mechanisms involved in its modulation. In conclusion,CFTR channel activity failure or CFTR inhibition regulates the expressionof different EGFR ligands possible involved in phenotypechanges present in CF-like cells. Acknowledgements: grants fromANPCYT (PICT 2012-1278), CONICET (PIP 2012-0685), and UCA;and research fellowships from CONICET (MMMC, MC and CM).