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Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK

Oncogene volume 31, pages 4128–4138 (2012)Cite this article

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Abstract

The membrane-anchored matrix metalloproteinase-regulator RECK is often downregulated in cancers; in some cases, a significant correlation between the level of residual RECK in resected tumors and patient survival has been noted. Furthermore, restoration of RECK expression in certain cancer-derived cell lines results in reduced tumorigenicity. Here we report that acute RECK expression in colon carcinoma cells results in cell cycle-arrest accompanied by downregulation of a ubiquitin ligase component, S-phase kinase-associated protein 2 (SKP2), and upregulation of its substrate, p27KIP1. Our data indicate that RECK-induced growth suppression is at least partially dependent on p27, and that RECK and type I collagen share similar effects on the SKP2–p27 pathway. Importantly, in patients with lung, colorectal and bladder cancers, the RECK/SKP2 ratio is high in normal tissues and lower in the cancer tissues. These findings reveal a novel molecular pathway linking cell-cycle progression to RECK downregulation, extracellular matrix degradation and SKP2 upregulation, and suggest that treatment regimens that induce RECK expression could be promising cancer therapies.

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Acknowledgements

We thank Chiaki Takahashi for the RECK cDNA, Mako Yamamoto for R1B2-6 cells, Hitoshi Kitayama and Tomoko Matsuzaki for discussions, David Alexander for critical reading of the manuscript, Hai-Ou Gu and Aiko Nishimoto for technical assistance and Aki Miyazaki for secretarial assistance. This work was supported by JSPS Grant-in-Aid for Creative Scientific Research and MEXT Grant-in-Aid on Priority Areas.

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  1. Department of Molecular Oncology and Global COE Program, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan,

    Y Yoshida, K Ninomiya & M Noda

  2. Department of Life Sciences, Laboratory of Oncology, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

    H Hamada

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  1. Y Yoshida
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Correspondence to M Noda.

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Yoshida, Y., Ninomiya, K., Hamada, H. et al. Involvement of the SKP2–p27KIP1 pathway in suppression of cancer cell proliferation by RECK. Oncogene 31, 4128–4138 (2012). https://doi.org/10.1038/onc.2011.570

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