MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma.
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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DOI：
10.18632/oncotarget.3729
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发表时间：
2015-06-20
期刊：
影响因子：
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通讯作者：
Jeon YK
中科院分区：
文献类型：
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作者：
Go H;Jang JY;Kim PJ;Kim YG;Nam SJ;Paik JH;Kim TM;Heo DS;Kim CW;Jeon YK
在弥漫性大B细胞淋巴瘤（DLBCL）患者中评估miR-21、miR-17-92和miR-155的预后意义，并研究miR-21通过调节FOXO 1和PI 3 K/AKT/mTOR通路促进DLBCL肿瘤发生的新机制。与对照组相比，DLBCL组织（n=200）中miR-21、miR-17-92和miR-155的表达显著上调（P=0.012、P=0.001和P<0.0001）。miR-21和miR-17-92的过表达与较短的无进展生存期（P=0.003和P=0.014）和总生存期（P=0.004和P=0.012）显著相关。高miR-21是利妥昔单抗联合化疗治疗DLBCL患者的独立预后因素。miR-21水平与DLBCL细胞系中FOXO 1和PTEN水平呈负相关。报告基因分析显示miR-21直接靶向抑制DLBCL细胞FOXO 1的表达，进而抑制Bim的转录。MiR-21还下调PTEN表达，从而激活PI 3 K/AKT/mTOR通路，这进一步降低FOXO 1表达。此外，miR-21抑制剂抑制MDR 1的表达和活性，从而使DLBCL细胞对阿霉素敏感。这些数据表明，miR-21通过在多个水平上调节PI 3 K/AKT/mTOR/FOXO 1通路在DLBCL中发挥重要的致癌作用，导致强烈的预后意义。因此，靶向miR-21可能在DLBCL中具有治疗相关性。
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.