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Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs

Abstract

Cancer cells show characteristic gene expression profiles. Recent studies support the potential importance of microRNA (miRNA) expression signatures as biomarkers and therapeutic targets. The membrane-anchored protease regulator RECK is downregulated in many cancers, and forced expression of RECK in tumor cells results in decreased malignancy in animal models. RECK is also essential for mammalian development. In this study, we found that RECK is a target of at least three groups of miRNAs (miR-15b/16, miR-21 and miR-372/373); that RECK mutants lacking the target sites for these miRNA show augmented tumor/metastasis-suppressor activities; and that miR-372/373 are upregulated in response to hypoxia through HIF1α and TWIST1, whereas miR-21 is upregulated by RAS/ERK signaling. These data indicate that the hypoxia- and RAS-signaling pathways converge on RECK through miRNAs, cooperatively downregulating this tumor suppressor and thereby promoting malignant cell behavior.

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Acknowledgements

We thank Takao Miki, EPS Chandana and Awad Shamma for valuable discussion; Masahiro Sonoshita for advice on animal experiments; Aiko Nishimoto and Hai-Ou Gu for technical support; Aki Miyazaki for secretarial assistance and David B Alexander and Oana Maria Cusen for critical reading of the paper. This work was supported by a Grant-in-Aid for Creative Scientific Research from JSPS. FL has been supported by fellowships from MEXT and the Global COE Program, JSPS.

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Correspondence to M Noda.

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Loayza-Puch, F., Yoshida, Y., Matsuzaki, T. et al. Hypoxia and RAS-signaling pathways converge on, and cooperatively downregulate, the RECK tumor-suppressor protein through microRNAs. Oncogene 29, 2638–2648 (2010). https://doi.org/10.1038/onc.2010.23

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