MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma
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Heounjeong Go1,2,3,*, Ji-Young Jang1,2,4,*, Pil-Jong Kim5, Young-Goo Kim1,2,4, Soo Jeong Nam1,2, Jin Ho Paik6, Tae Min Kim7, Dae Seog Heo7, Chul-Woo Kim1,2,4 and Yoon Kyung Jeon1,2,4
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
* These authors have contributed equally to this work
Yoon Kyung Jeon, email:
Keywords: diffuse large B-cell lymphoma, miR-21, miR-17-92 cluster, miR-155, FOXO1
Received: January 17, 2015 Accepted: March 11, 2015 Published: March 30, 2015
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.
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