Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers

Abstract

Genetic alterations of APC and CTNNB1 (β-catenin) have been identified in a number of human cancers including tumors arising in the colon and liver. Mutations in these genes lead to abnormal accumulation of β-catenin and constitutive activation of target genes in the Wnt signaling pathway. To clarify the precise role of accumulated β-catenin in colorectal carcinogenesis, we searched for genes involved in the β-catenin/Tcf signaling pathway by cDNA microarray. MT1–MMP (membrane-type matrix metalloproteinase) was among 84 genes that were down-regulated after β-catenin had been depleted by transduction of wild-type APC in SW480 cells. Expression of MT1–MMP was elevated in 22 of 24 colon carcinomas we examined. Reporter assays and an electromobility-shift assay revealed a DNA fragment between −1169 bp and −1163 bp in the 5′ flanking region of this gene to be a target of the β-catenin/Tcf4 complex. Our results indicate that MT1–MMP is a direct down-stream target in the Wnt signaling pathway, and that one of the ways accumulated β-catenin contributes to colorectal carcinogenesis is by transactivating this gene.