1. Overexpression of the retinoic acid-responsive gene Stra6 in human cancers and its synergistic induction by Wnt-1 and retinoic acid
- Author
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Szeto, W., Jiang, W., Tice, D. A., Bonnee Rubinfeld, Hollingshead, P. G., Fong, S. E., Dugger, D. L., Pham, T., Yansura, D. G., Wong, T. A., Grimaldi, J. C., Corpuz, R. T., Singh, J. S., Frantz, G. D., Devaux, B., Crowley, C. W., Schwall, R. H., Eberhard, D. A., Rastelli, L., Polakis, P., and Pennica, D.
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Chromosomes, Human, Pair 15 ,Mice, Inbred BALB C ,DNA, Complementary ,Reverse Transcriptase Polymerase Chain Reaction ,Gene Expression Profiling ,Mammary Neoplasms, Experimental ,Membrane Proteins ,Antineoplastic Agents ,Mice, Transgenic ,Tretinoin ,Wnt1 Protein ,Adenocarcinoma ,Zebrafish Proteins ,Gene Expression Regulation, Neoplastic ,Wnt Proteins ,Mice ,Proto-Oncogene Proteins ,Colonic Neoplasms ,Tumor Cells, Cultured ,Animals ,Humans ,RNA, Messenger ,Signal Transduction - Abstract
Genetic defects in the Wnt-1 signaling pathway contribute to human tumor progression and are especially prevalent in colorectal cancer. We screened mouse 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 harbor defects in Wnt-1 signaling. Stimulation of C57MG cells with retinoic acid plus Wnt-1 resulted in expression of Stra6 transcript to levels greatly exceeding that observed with either stimulus alone. This synergy could be explained in part by the up-regulation of retinoic acid receptor-gamma that was observed in response to Wnt-1 signaling. Accordingly, treatment of human colorectal cancer cell lines with retinoic acid resulted in the up-regulation of Stra6 mRNA and accumulation of Stra6 protein at the cell membrane. The data support a model in which Wnt-1 signaling synergizes with retinoids to activate retinoic acid receptor-gamma-responsive genes in human cancers.