Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers.
Genetic alterations of APC and CTNNB1 (beta-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 beta-catenin and constitutive activation of target genes in the Wnt signaling pathway. To clarify the precise role of accumulated beta-catenin in colorectal carcinogenesis, we searched for genes involved in the beta-catenin/Tcf signaling pathway by cDNA microarray. MT1-MMP (membrane-type matrix metalloproteinase) was among 84 genes that were down-regulated after beta-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 beta-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 beta-catenin contributes to colorectal carcinogenesis is by transactivating this gene.
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.
Meiko
M
Takahashi
Tatsuhiko
T
Tsunoda
Motoharu
M
Seiki
Yusuke
Y
Nakamura
Yoichi
Y
Furukawa
D024506:5' Flanking Region; D001665:Binding Sites; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000378:metabolism*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases