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Oncogenes, Fusion Genes and Tumor Suppressor Genes

The role of microRNA-150 as a tumor suppressor in malignant lymphoma

Leukemia volume 25, pages 1324–1334 (2011)Cite this article

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Abstract

MicroRNA (miRNA; miR) is a class of small regulatory RNA molecules, the aberrant expression of which can lead to the development of cancer. We recently reported that overexpression of miR-21 and/or miR-155 leads to activation of the phosphoinositide 3-kinase (PI3K)–AKT pathway in malignant lymphomas expressing CD3−CD56+ natural killer (NK) cell antigen. Through expression analysis, we show in this study that in both NK/T-cell lymphoma lines and samples of primary lymphoma, levels of miR-150 expression are significantly lower than in normal NK cells. To examine its role in lymphomagenesis, we transduced miR-150 into NK/T-cell lymphoma cells, which increased the incidence of apoptosis and reduced cell proliferation. Moreover, the miR-150 transductants appeared senescent and showed lower telomerase activity, resulting in shortened telomeric DNA. We also found that miR-150 directly downregulated expression of DKC1 and AKT2, reduced levels of phosphorylated AKTser473/4 and increased levels of tumor suppressors such as Bim and p53. Collectively, these results suggest that miR-150 functions as a tumor suppressor, and that its aberrant downregulation induces continuous activation of the PI3K–AKT pathway, leading to telomerase activation and immortalization of cancer cells. These findings provide new insight into the pathogenesis of malignant lymphoma.

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Acknowledgements

This work is supported in by a Grant-in-Aid from the Japan Society for the Promotion of Science (HT). We wish to express our appreciation to Ms E Kobayashi, Y Abe, Y Chiba and H Kataho for their outstanding technical assistance, Dr T Nanjo (Akita University, Akita, Japan) and Dr R Ichinohasama (Tohoku University, Sendai, Japan) for their histological and/or clinical diagnosis of lymphoma. Antibody against BCAP was kindly provided from Professor T Kurosaki (RIKEN). pMX vector was kindly provided by Dr T Kitamura (Tokyo University, Tokyo, Japan).

Author contributions

AW performed all experiments, analyzed data, designed experiments and constructed figures and tables. HT designed and performed experiments, analyzed data, wrote the paper and organized the study. JY, KT, MN, KI, MK, YK, NT, TN, SN and KS performed experiments and analyzed data.

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Author notes

  1. A Watanabe and H Tagawa: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    A Watanabe, H Tagawa, K Teshima, M Nara, K Iwamoto, Y Kameoka, N Takahashi & K Sawada

  2. Radioisotope Research Laboratory, Bioscience Education-Reserch Center, Akita University, Akita, Japan

    J Yamashita

  3. Department of Internal Medicine, Hiraka General Hospital, Akita, Japan

    M Kume

  4. Department of Surgery, Senboku Kumiai General Hospital, Akita, Japan

    T Nakagawa

  5. Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan

    N Shimizu

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  1. A Watanabe
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  2. H Tagawa
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Correspondence to H Tagawa.

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Watanabe, A., Tagawa, H., Yamashita, J. et al. The role of microRNA-150 as a tumor suppressor in malignant lymphoma. Leukemia 25, 1324–1334 (2011). https://doi.org/10.1038/leu.2011.81

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