SPROUTY-2 (SPRY2) is a modulator of tyrosine kinase receptor signaling with receptor- and cell type-dependent inhibitory or enhancing effects. Previously we reported that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1o,25-dihydroxyvitamin D3 through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1o,25-dihydroxyvitamin D3 -induced E-cadherin expression (Barbáchano et al., Oncogene, 2010). Later we found that in human colon cancer cells SPRY2 expression is induced by betacatenin in cooperation with the transcription factor FOX03a instead of TCF/LEF1 proteins. Importantly, the amount of SPRY2 protein correlates with shorter overall survival of colon cancer patients (Ordóñez-Morán et al., Oncogene, 2014). Global transcriptomic analyses show that SPRY2 dysregulates tight junctions, and epithelial polarity genes. A key action of SPRY2 is the upregulation of the major EMT inducer ZEBl, as these effects are reversed by ZEB1 knock-down by means of RNA interference. Consistently, we found an inverse correlation between the expression level of claudin-7 and those of SPRY2 and ZEBl in human colon tumors. Our data show that ZEBl upregulation by SPRY2 results from the combined induction of ETSl transcription factor and the repression of miR-150 and miR-200 family that target ZEBl RNA. Moreover, SPRY2 increases AKT activation and the blockade of AKT inhibits SPRY2 action. Altogether, our results show a tumorigenic role of SPRY2 in colon cancer that is based on the induction of epithelial-tomesenchymal transition via upregulation of ZEBl.

Resumen del trabajo presentado al V Encuentro Científico de Jóvenes Investigadores de la Red Temática de Investigación Cooperativa en Cáncer, celebrado en Pamplona, Navarrra el 5 de octubre de 2015.

Peer Reviewed