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Oncotarget. 2015 Jun 20;6(17):15035-49.

MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.

Go H1,2,3, Jang JY1,2,4, Kim PJ5, Kim YG1,2,4, Nam SJ1,2, Paik JH6, Kim TM7, Heo DS7, Kim CW1,2,4, Jeon YK1,2,4.

Author information

1
Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
2
The Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
3
Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
4
The Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, South Korea.
5
Biomedical Knowledge Engineering Laboratory, Seoul National University School of Denistry, Seoul, South Korea.
6
Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi, South Korea.
7
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.

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.

KEYWORDS:

FOXO1; diffuse large B-cell lymphoma; miR-155; miR-17-92 cluster; miR-21

PMID:
25909227
PMCID:
PMC4558134
DOI:
10.18632/oncotarget.3729
[Indexed for MEDLINE]
Free PMC Article

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