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MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression

Oncogene volume 31, pages 1623–1635 (2012)Cite this article

Abstract

The tyrosine kinase c-Src is upregulated in various human cancers; however, the molecular mechanisms underlying c-Src-mediated tumor progression remain unclear. Here we show that downregulation of microRNA (miR)-542-3p is tightly associated with tumor progression via c-Src-related oncogenic pathways. In c-Src-transformed fibroblasts and human cancer cells that overexpress c-Src, miR-542-3p is substantially downregulated, and the ectopic expression of miR-542-3p suppresses tumor growth. We identified the integrin-linked kinase (ILK) as a conserved target of miR-542-3p. ILK upregulation promotes cell adhesion and invasion by activating the integrin–focal adhesion kinase (FAK)/c-Src pathway, and can also contribute to tumor growth via the AKT and glycogen synthase kinase 3β pathways. MiR-542-3p expression is downregulated by the activation of c-Src-related signaling molecules, including epidermal growth factor receptor, K-Ras and Ras/Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase. In human colon cancer tissues, downregulation of miR-542-3p is significantly correlated with the upregulation of c-Src and ILK. Our results suggest that the novel c-Src–miR-542-3p–ILK–FAK circuit plays a crucial role in controlling tumor progression.

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Acknowledgements

We thank Drs A Imamoto, T Akagi and M Yutsudo for their 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, Osaka, Japan

    C Oneyama, Y Takahashi, N Wakabayashi & M Okada

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

    E Morii, J Ikeda & K Aozasa

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

    D Okuzaki

  4. Surgery, Osaka Police Hospital, Osaka, Japan

    H Akamatsu & T Nishida

  5. Pathology, Osaka Police Hospital, Osaka, Japan

    M Tsujimoto

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  1. C Oneyama
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Correspondence to C Oneyama.

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Oneyama, C., Morii, E., Okuzaki, D. et al. MicroRNA-mediated upregulation of integrin-linked kinase promotes Src-induced tumor progression. Oncogene 31, 1623–1635 (2012). https://doi.org/10.1038/onc.2011.367

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