Overexpression of the retinoic acid-responsive gene Stra6 in human cancersand its synergistic induction by Wnt-1 and retinoic acid

Genetic defects in the Wnt-1 signaling pathway contribute to human tumor pr ogression and are especially prevalent in colorectal cancer. We screened mo use C57MG cells to isolate mRNAs induced by Wnt-1 and identified Stra6, an mRNA known to be up-regulated by retinoic acid. Up-regulation of Stra6 mRNA was also observed in hyperplastic mammary tissue and mammary gland tumors from transgenic mice expressing Wnt-1 and in human tumors that frequently h arbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatl y exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma tha t was observed in response to Wnt-1 signaling. Accordingly, treatment of hu man colorectal cancer cell lines with retinoic acid resulted in the up-regu lation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane . The data support a model in which Wnt1 signaling synergizes with retinoid s to activate retinoic acid receptor-gamma -responsive genes in human cance rs.