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

Abstract

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<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<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

Targeting PI3‐kinase (PI3K), AKT and mTOR axis in lymphoma

“…Although PTEN can be lost through genomic deletions, it is likely that in some lymphomas loss of PTEN protein is related to post‐transcriptional regulatory measures, such as the repressive effects of the oncomir MIR21 (hsa‐miR‐21), which is upregulated in a number of solid and haematological cancers, including DLBCL (Bai et al , ), or phosphorylation, which has been demonstrated to be functionally relevant in MCL (Dal Col et al , ). In a recent abstract presented at the 2014 American Association for Cancer Research meeting, the role of MIR21 in DLBCL was examined by comparing MIR21MIRexpression by quantitative polymerase chain reaction in DLBCL primary tumours, DLBCL cell lines and normal tonsils (Go et al , ). Investigators showed a strong inverse correlation between MIR21 expression and PTEN and FOXO1 expression in cell lines, and statistically significant inverse correlation between MIR21 expression and progression‐free survival (PFS; P = 0·001) and overall survival ( P = 0·002), further strengthening the evidence of MIR21's role in the PI3K pathway and DLBCL.…”