title: MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.
abstract: The prognostic implications of miR-21, miR-17-92 and miR-155 were evaluated in diffuse large B-cell lymphoma (DLBCL) patients, and novel mechanism by which miR-21 contributes to the oncogenesis of DLBCL by regulating FOXO1 and PI3K/AKT/mTOR pathway was investigated. The expressions of miR-21, miR-17-92 and miR-155 measured by quantitative reverse-transcription-PCR were significantly up-regulated in DLBCL tissues (n=200) compared to control tonsils (P=0.012, P=0.001 and P<0.0001). Overexpression of miR-21 and miR-17-92 was significantly associated with shorter progression-free survival (P=0.003 and P=0.014) and overall survival (P=0.004 and P=0.012). High miR-21 was an independent prognostic factor in DLBCL patients treated with rituximab-combined chemotherapy. MiR-21 level was inversely correlated with the levels of FOXO1 and PTEN in DLBCL cell lines. Reporter-gene assay showed that miR-21 directly targeted and suppressed the FOXO1 expression, and subsequently inhibited Bim transcription in DLBCL cells. MiR-21 also down-regulated PTEN expression and consequently activated the PI3K/AKT/mTOR pathway, which further decreased FOXO1 expression. Moreover, miR-21 inhibitor suppressed the expression and activity of MDR1, thereby sensitizing DLBCL cells to doxorubicin. These data demonstrated that miR-21 plays an important oncogenic role in DLBCL by modulating the PI3K/AKT/mTOR/FOXO1 pathway at multiple levels resulting in strong prognostic implication. Therefore, targeting miR-21 may have therapeutic relevance in DLBCL.
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Heounjeong
authors.initials: H
authors.lastname: Go
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Jang
authors.affiliation: Biomedical Knowledge Engineering Laboratory, Seoul National University School of Denistry, Seoul, South Korea.
authors.forename: Pil-Jong
authors.initials: PJ
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Young-Goo
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Nam
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi, South Korea.
authors.forename: Jin Ho
authors.initials: JH
authors.lastname: Paik
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Kim
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.|The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Jeon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D015153:Blotting, Western / Q000706:statistics & numerical data; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000706:statistics & numerical data; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008565:Membrane Proteins; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C000606775:BCL2L11 protein, human; C085126:FOXO1 protein, human; C524940:MIRN21 microRNA, human
keywords: FOXO1; diffuse large B-cell lymphoma; miR-155; miR-17-92 cluster; miR-21