Abstract 1490: MiR-21 has strong prognostic implications and functions as an oncogenic miR by modulating PI3K/Akt pathway at multiple levels in diffuse large B cell lymphoma
Authors: Go Heounjeong , Jang Ji-Young , Nam Soo Jeong , Kim Young-Goo , Paik Jin H. , Kim Tae Min , Heo Dae Seog , Kim Chul-Woo , Jeon Yoon Kyung 
Published: May 2015

MicroRNA (miR)-21, -17-92 cluster and -155 have been known to play important roles in the development and progression of various cancer types. However, effects of their expression level on the patient's prognosis in diffuse large B cell lymphoma (DLBCL) have not been fully elucidated. Thus, we investigated the association of miR-21, -17-92 cluster and -155 expressions with clinicopathologic features and prognosis in patients with DLBCL. Quantitative real-time reverse transcriptase-polymerase chain reaction analysis was performed to evaluate the expression level of miR-21, -17-92 cluster and -155 in 200 cases of DLBCL, and 11 tonsils as control, using formalin-fixed paraffin-embedded tissues. Role of miR-21 in DLBCL was also analyzed using several DLBCL cell lines. MiR-21, -17-92 cluster and -155 expressions were significantly increased in DLBCL compared with control (p=0.012, p=0.001 and p&lt;0.0001, respectively). MiR-21 up-regulation was more frequently observed with higher stage (p=0.004) and higher International Prognostic Index (IPI) (p=0.043) and miR-17-92 cluster up-regulation was more common with older age (p=0.019) and higher performance status (PS) (p=0.012). Moreover, miR-21 and -17-92 cluster up-regulations were significantly associated with decreased progression free survival (PFS) (p=0.001 and p=0.014, respectively) and overall survival (OS) (p=0.002 and p=0.012, respectively). In the Cox proportional hazard model, overexpression of miR-21 was found to be an independently poor predictor for OS (HR=1.72; p=0.043). Importantly, high miR-21 expression showed stronger prediction for OS in rituximab treated (HR=2.62; p=0.017) and germinal center B-like (HR=11.91; p&lt;0.001) subgroups. MiR-21 expression was inversely correlated with PTEN and FOXO1 expression in DLBCL cell lines. PTEN and FOXO1 expressions were increased by inhibition of miR-21 in SU-DHL4 and SU-DHL5 cell lines. Inhibition of miR-21 suppressed cell proliferation and sensitized these cells to doxorubicin cytotoxicity, which was accompanied by down-regulation of phospho-Akt. In addition, Bim, a transcriptional target of FOXO1, was increased by miR-21 inhibitor at the transcriptional level. Expression and functional activity of MDR1, which is known to be up-regulated by mTOR, were suppressed by miR-21 inhibitor. Together these data suggest that miR-21 might contribute to activation of PI3K/Akt pathway by down-regulating PTEN at an upstream level, and moreover suppress the expression of FOXO1, a tumor suppressive transcription factor at a downstream level, putatively in a direct and indirect manner. In conclusion, up-regulation of miR-21 is considered to play an important oncogenic role in DLBCL and have a strong prognostic implication.

Citation Format: Heounjeong Go, Ji-Young Jang, Soo Jeong Nam, Young-Goo Kim, Jin Ho Paik, Tae Min Kim, Dae Seog Heo, Chul-Woo Kim, Yoon Kyung Jeon. MiR-21 has strong prognostic implications and functions as an oncogenic miR by modulating PI3K/Akt pathway at multiple levels in diffuse large B cell lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1490. doi:10.1158/1538-7445.AM2014-1490