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.
MeSH terms
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Animals
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Antineoplastic Agents / pharmacology*
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Chromosomes, Human, Pair 15
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Colonic Neoplasms / genetics*
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Colonic Neoplasms / metabolism
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DNA, Complementary / genetics
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DNA, Complementary / isolation & purification
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / metabolism
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Membrane Proteins / biosynthesis*
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Membrane Proteins / genetics*
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Mice
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Mice, Inbred BALB C
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Mice, Transgenic
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology*
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / physiology
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Tretinoin / pharmacology*
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Tumor Cells, Cultured
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Wnt Proteins
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Wnt1 Protein
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Zebrafish Proteins*
Substances
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Antineoplastic Agents
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DNA, Complementary
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Membrane Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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Stra6 protein, mouse
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WNT1 protein, human
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Wnt Proteins
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Wnt1 Protein
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Wnt1 protein, mouse
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Zebrafish Proteins
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Tretinoin