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MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways

Oncogene volume 30, pages 3489–3501 (2011)Cite this article

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Abstract

The tyrosine kinase c-Src is upregulated in various human cancers, but the molecular mechanisms underlying c-Src-mediated tumor growth remain unclear. Here we examined the involvement of microRNAs in the c-Src-mediated tumor growth. Microarray profiling revealed that c-Src activation downregulates a limited set of microRNAs, including miR-99a, which targets oncogenic mammalian target of rapamycin (mTOR) and fibroblast growth factor receptor 3 (FGFR3). Re-expression of miR-99a suppressed tumor growth of c-Src-transformed cells, and this effect was restored by the overexpression of mTOR. The downregulation of miR-99a was also observed in epidermal growth factor- and Ras-transformed cells, and it was suppressed by inhibiting the mitogen-activated protein kinase (MAPK) pathway. Furthermore, miR-99a downregulation is associated with mTOR/FGFR3 upregulation in various human lung cancer cells/tissues. The tumorigenicity of these cells was suppressed by the introduction of miR-99a. These findings suggest that the miR-99a-mTOR/FGFR3 pathway is crucial for controlling tumor growth in a wide range of human cancers that harbor upregulation of the Src-related oncogenic pathways.

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Acknowledgements

We thank Drs A Imamoto, T Akagi and M Yutsudo for generous gifts of reagents. This work was supported by a Grant-in-aid for Young Scientists from the Ministry of Education, Culture, Sports, Science and Technology of Japan and The Exciting Leading-Edge Research Project at Osaka University.

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Authors and Affiliations

  1. Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    C Oneyama, K Suzuki, T Kanou & M Okada

  2. Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    J Ikeda, E Morii & K Aozasa

  3. DNA-chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan

    D Okuzaki

  4. Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    T Kanou, Y Shintani & M Okumura

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  1. C Oneyama
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Correspondence to C Oneyama.

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Oneyama, C., Ikeda, J., Okuzaki, D. et al. MicroRNA-mediated downregulation of mTOR/FGFR3 controls tumor growth induced by Src-related oncogenic pathways. Oncogene 30, 3489–3501 (2011). https://doi.org/10.1038/onc.2011.63

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