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Blood, 8 October 2009, Vol. 114, No. 15, pp. 3265-3275. Prepublished online as a Blood First Edition Paper on July 29, 2009; DOI 10.1182/blood-2009-06-222794. This Article Full Text Full Text (PDF) Supplemental Table All Versions of this Article: blood-2009-06-222794v1 114/15/3265    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Yamanaka, Y. Articles by Sawada, K.-i. PubMed PubMed Citation Articles by Yamanaka, Y. Articles by Sawada, K.-i. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer–cell lymphoma/leukemia Yasuo Yamanaka1,*, Hiroyuki Tagawa1,*, Naoto Takahashi1, Atsushi Watanabe1, Yong-Mei Guo1, Keiko Iwamoto1, Junsuke Yamashita2, Hirobumi Saitoh1, Yoshihiro Kameoka1, Norio Shimizu3, Ryo Ichinohasama4, and Ken-ichi Sawada1 1 Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita; 2 Radioisotope Research Laboratory, Bioscience Education-Research Center, Akita University School of Medicine, Akita; 3 Division of Virology and Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo; and 4 Division of Histology, Tohoku University Graduate School of Medicine, Sendai, Japan The gene(s) responsible for natural killer (NK)–cell lymphoma/leukemia have not been identified. In the present study, we found that in NK-cell lymphoma lines (n = 10) and specimens of primary lymphoma (n = 10), levels of miR-21 and miR-155 expression were inversely related and were significantly greater than those found in normal natural killer (CD3–CD56+) cells (n = 8). To determine the functions of these microRNAs in lymphomagenesis, we examined the effects of antisense oligonucleotides (ASOs) targeting miR-21 (ASO-21) and/or miR-155 (ASO-155) in NK-cell lymphoma lines overexpressing one or both of these miRNAs. Conversely, cells showing little endogenous expression of miR-21 or miR-155 were transduced by the use of lentiviral vectors, leading to their overexpression. Reducing expression of miR-21 or miR-155 led to up-regulation of phosphatase and tensin homologue (PTEN), programmed cell death 4 (PDCD4), or Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1). ASO-21– and ASO-155–treated cell lines all showed down-regulation of phosphorylated AKTser473. Moreover, transduction with either miR-21 or miR-155 led to down-regulation of PTEN and PDCD4 or SHIP1 with up-regulation of phosphorylated AKTser473. Collectively, these results provide important new insight into the pathogenesis of NK-cell lymphoma/leukemia and suggest targeting miR-21 and/or miR-155 may represent a useful approach to treating NK-cell lymphoma/leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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