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EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis

Oncogene volume 33, pages 2454–2463 (2014)Cite this article

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Abstract

Despite frequent KRAS mutation, the early molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC) development have not been fully elucidated. By tracking a potential regulator of another feature of PDAC precursors, acquisition of foregut or gastric epithelial gene signature, we herein report that aberrant overexpression of ecotropic viral integration site 1 (EVI1) oncoprotein, which is usually absent in normal pancreatic duct, is a widespread marker across the full spectrum of human PDAC precursors and PDAC. In pancreatic cancer cells, EVI1 depletion caused remarkable inhibition of cell growth and migration, indicating its oncogenic roles. Importantly, we found that EVI1 upregulated KRAS expression through suppression of a potent KRAS suppressor, miR-96, in pancreatic cancer cells. Collectively, the present findings suggest that EVI1 overexpression and KRAS mutation converge on activation of the KRAS pathway in early phases of pancreatic carcinogenesis and propose EVI1 and/or miR-96 as early markers and therapeutic targets in this dismal disease.

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Acknowledgements

We thank all members of the Department of Pathology, University of Tokyo. This work was supported by the Industrial Technology Research Grant Program (2008) from the New Energy and Industrial Technology Development Organization (NEDO) of Japan (SI), the Grant-in-Aid for Scientific Research on Innovative Areas (SI),46 the Grant-in-Aid for Young Scientists (A),46 the GCOE Program for ‘Integrative Life Science Based on the Study of Biosignaling Mechanisms’ (HIS, KM), and for ‘Chemical Biology of the Diseases’ (MF and MK) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Cell Science Research Foundation (HIS, KM).

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Authors and Affiliations

  1. Department of Pathology, University of Tokyo, Tokyo, Japan

    M Tanaka, J Shibahara, A Kunita, S Ishikawa & M Fukayama

  2. Department of Molecular Pathology, University of Tokyo, Tokyo, Japan

    H I Suzuki & K Miyazono

  3. Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan

    T Isagawa

  4. Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    A Yoshimi & M Kurokawa

  5. Genome Science Division, RCAST, University of Tokyo, Tokyo, Japan

    H Aburatani

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  1. M Tanaka
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Correspondence to M Fukayama.

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Tanaka, M., Suzuki, H., Shibahara, J. et al. EVI1 oncogene promotes KRAS pathway through suppression of microRNA-96 in pancreatic carcinogenesis. Oncogene 33, 2454–2463 (2014). https://doi.org/10.1038/onc.2013.204

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