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Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

Oncogene volume 31, pages 3949–3960 (2012)Cite this article

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Abstract

Inflammation has an important role in cancer development through various mechanisms. It has been shown that dysregulation of microRNAs (miRNAs) that function as oncogenes or tumor suppressors contributes to tumorigenesis. However, the relationship between inflammation and cancer-related miRNA expression in tumorigenesis has not yet been fully understood. Using K19-C2mE and Gan mouse models that develop gastritis and gastritis-associated tumors, respectively, we found that 21 miRNAs were upregulated, and that 29 miRNAs were downregulated in gastric tumors in an inflammation-dependent manner. Among these miRNAs, the expression of miR-7, a possible tumor suppressor, significantly decreased in both gastritis and gastric tumors. Moreover, the expression of miR-7 in human gastric cancer was inversely correlated with the levels of interleukin-1β and tumor necrosis factor-α, suggesting that miR-7 downregulation is related to the severity of inflammatory responses. In the normal mouse stomach, miR-7 expression was at a basal level in undifferentiated gastric epithelial cells, and was induced during differentiation. Moreover, transfection of a miR-7 precursor into gastric cancer cells suppressed cell proliferation and soft agar colony formation. These results suggest that suppression of miR-7 expression is important for maintaining the undifferentiated status of gastric epithelial cells, and thus contributes to gastric tumorigenesis. Although epigenetic changes were not found in the CpG islands around miR-7-1 of gastritis and gastric tumor cells, we found that activated macrophage-derived small molecule(s) (<3 kDa) are responsible for miR-7 repression in gastric cancer cells. Furthermore, the miR-7 expression level significantly decreased in the inflamed gastric mucosa of Helicobacter-infected mice, whereas it increased in the stomach of germfree K19-C2mE and Gan mice wherein inflammatory responses were suppressed. Taken together, these results indicate that downregulation of tumor suppressor miR-7 is a novel mechanism by which the inflammatory response promotes gastric tumorigenesis.

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Acknowledgements

We thank Manami Watanabe for her excellent technical assistance. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and the Ministry of Health, Labour and Welfare of Japan.

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Author notes

  1. Y-S Piao

    Present address: 8Current address: Department of Pathophysiology, Medical College, Yanbian University, Yanji City 133002, China.,

  2. D Kong and Y-S Piao: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    D Kong, Y-S Piao, H Oshima, K Oguma, T-O Ishikawa & M Oshima

  2. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan

    S Yamashita & T Ushijima

  3. Department of Gastroenterologic Surgery, Kanazawa University Hospital, Kanazawa, Japan

    S Fushida & T Fujimura

  4. Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

    T Minamoto

  5. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    H Seno

  6. Faculty of Electrical and Computer Engineering, Institute of Science and Engineering, Kanazawa University, Kanazawa, Japan

    Y Yamada & K Satou

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  1. D Kong
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Correspondence to M Oshima.

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Kong, D., Piao, YS., Yamashita, S. et al. Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells. Oncogene 31, 3949–3960 (2012). https://doi.org/10.1038/onc.2011.558

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  • DOI: https://doi.org/10.1038/onc.2011.558

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