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

Oncogene volume 21, pages 5861–5867 (2002)Cite this article

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.

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Acknowledgements

We are grateful to Tae Makino and Yuka Yamane-Tanaka for technical assistance. This work was supported in part by Research for the Future Program Grant (00L01402) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Meiko Takahashi, Yusuke Nakamura & Yoichi Furukawa

  2. Laboratory for Medical Informatics, SNP Research Center, Riken (Institute of Physical and Chemical Research), Minato-ku, Tokyo, Japan

    Tatsuhiko Tsunoda

  3. Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan

    Motoharu Seiki

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  1. Meiko Takahashi
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  2. Tatsuhiko Tsunoda
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  3. Motoharu Seiki
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Correspondence to Yusuke Nakamura.

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Takahashi, M., Tsunoda, T., Seiki, M. et al. Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers. Oncogene 21, 5861–5867 (2002). https://doi.org/10.1038/sj.onc.1205755

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