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Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors

Oncogene volume 22, pages 8716–8722 (2003)Cite this article

Abstract

Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) has been believed a key enzyme in tumor invasion, because it is expressed in a variety of malignant human tumors, and overexpression of the enzyme enhances the ability of cellular invasiveness. However, it has not necessarily been clarified whether the endogenously expressed MT1-MMP in human tumors plays a critical role in their invasiveness. We used RNA silencing technology to downregulate the endogenous MT1-MMP expression in human tumor cells (fibrosarcoma HT1080 and gastric carcinoma MKN-28 cell lines), and evaluated the effect on the invasion of a reconstituted basement membrane (Matrigel). Transfection of a double-stranded RNA targeted to the MT1-MMP gene decreased the level of the enzyme to less than 10–20% without affecting production of other MMPs. According to the degree of silencing, activation of proMMP-2 was inhibited. CD44 shedding was also inhibited, but only in part. Decreased MT1-MMP levels were also reflected in reduced cell motility on hyaluronan (HA) and invasion in Matrigel. Thus, specific downregulation of MT1-MMP expression was sufficient to cause significant inhibition of the migration and invasion of tumor cells, even though other MMPs continued to be expressed.

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Abbreviations

MMP:

matrix metalloproteinase

MT-MMP:

membrane-type matrix metalloproteinase

TIMP:

tissue inhibitor of metalloproteinase

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Acknowledgements

We thank Drs Ikuo Yana, Naohiko Koshikawa, Hidetoshi Mori, Takamasa Uekita, Hirokazu Matsuki, Hiroyuki Nakamura, and Yoshifumi Itoh for valuable discussion. This work was supported by the Special Coordination Fund for promoting Science and Technology from the Ministry of Science and Technology of Japan and by a grant-in-aid for Cancer Research from the Ministry of Education, Science and Culture of Japan.

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  1. Contributed equally to this work.

Authors and Affiliations

  1. Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan

    Junko Ueda, Masahiro Kajita, Naoko Suenaga & Motoharu Seiki

  2. Department of Orthopaedic Surgery, The Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo, Japan

    Junko Ueda & Katsuyuki Fujii

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  1. Junko Ueda
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Correspondence to Motoharu Seiki.

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Ueda, J., Kajita, M., Suenaga, N. et al. Sequence-specific silencing of MT1-MMP expression suppresses tumor cell migration and invasion: importance of MT1-MMP as a therapeutic target for invasive tumors. Oncogene 22, 8716–8722 (2003). https://doi.org/10.1038/sj.onc.1206962

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