title: The role of microRNA-150 as a tumor suppressor in malignant lymphoma.
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 AKT(ser473/4) 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.
authors.affiliation: Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Tagawa
authors.forename: J
authors.initials: J
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Teshima
authors.forename: M
authors.initials: M
authors.lastname: Nara
authors.forename: K
authors.initials: K
authors.lastname: Iwamoto
authors.forename: M
authors.initials: M
authors.lastname: Kume
authors.forename: Y
authors.initials: Y
authors.lastname: Kameoka
authors.forename: N
authors.initials: N
authors.lastname: Takahashi
authors.forename: T
authors.initials: T
authors.lastname: Nakagawa
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.forename: K
authors.initials: K
authors.lastname: Sawada
mesh_terms: D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D016147:Genes, Tumor Suppressor; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control; D035683:MicroRNAs / Q000032:analysis / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D016615:Telomere
chemical_list: D018797:Cell Cycle Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C112148:DKC1 protein, human; C533097:MIR150, human; C494921:AKT2 protein, human