title: Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia.
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 down-regulation of phosphorylated AKT(ser473). Moreover, transduction with either miR-21 or miR-155 led to down-regulation of PTEN and PDCD4 or SHIP1 with up-regulation of phosphorylated AKT(ser473). 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.
authors.affiliation: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tagawa
authors.forename: Naoto
authors.initials: N
authors.lastname: Takahashi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Watanabe
authors.forename: Yong-Mei
authors.initials: YM
authors.lastname: Guo
authors.forename: Keiko
authors.initials: K
authors.lastname: Iwamoto
authors.forename: Junsuke
authors.initials: J
authors.lastname: Yamashita
authors.forename: Hirobumi
authors.initials: H
authors.lastname: Saitoh
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kameoka
authors.forename: Norio
authors.initials: N
authors.lastname: Shimizu
authors.forename: Ryo
authors.initials: R
authors.lastname: Ichinohasama
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Sawada
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D007694:Killer Cells, Natural; D016086:Lentivirus; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D014161:Transduction, Genetic
chemical_list: D051017:Apoptosis Regulatory Proteins; C524942:MIRN155 microRNA, human; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D020319:Oligodeoxyribonucleotides, Antisense; C114487:PDCD4 protein, human; D012334:RNA, Neoplasm; D016601:RNA-Binding Proteins; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases