Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia

Yasuo Yamanaka, Hiroyuki Tagawa, Naoto Takahashi, Atsushi Watanabe, Yong Mei Guo, Keiko Iwamoto, Junsuke Yamashita, Hirobumi Saitoh, Yoshihiro Kameoka, Norio Shimizu, Ryo Ichinohasama, Ken Ichi Sawada

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164 Citations (Scopus)

Abstract

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 downregulation 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.

Original languageEnglish
Pages (from-to)3265-3275
Number of pages11
JournalBlood
Volume114
Issue number15
DOIs
Publication statusPublished - 2009 Nov 19

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Yamanaka, Y., Tagawa, H., Takahashi, N., Watanabe, A., Guo, Y. M., Iwamoto, K., Yamashita, J., Saitoh, H., Kameoka, Y., Shimizu, N., Ichinohasama, R., & Sawada, K. I. (2009). Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood, 114(15), 3265-3275. https://doi.org/10.1182/blood-2009-06-222794