MiR-10a inhibits cell proliferation and promotes cell apoptosis by targeting BCL6 in diffuse large B-cell lymphoma.

Qian Fan,Yi Ba,Xianming Liu,Wu Sun,Lanfang Li,Chen-Yu Zhang,Haiyang Zhang,Ke Zen,Zhen Zhou,Wei Li,Xi Chen,Huilai Zhang,Xiangrui Meng,Hongwei Liang

doi:10.1007/s13238-016-0316-z

Abstract

The BCL6 (B-Cell Lymphoma 6) gene is a proto-oncogene that is often expressed in diffuse large B-cell lymphomas (DLBCLs). BCL6 loss of function can kill DLBCL cells, demonstrating that BCL6 is necessary for the survival of DLBCL cells and could be a therapeutic target. In this study, we found that BCL6 protein levels were consistently upregulated in DLBCL tissues, whereas its mRNA levels varied randomly in tissues, suggesting that a post-transcriptional mechanism was involved in BCL6 regulation. We used bioinformatics analysis to search for miRNAs, which potentially target BCL6, and identified specific targeting sites for miR-10a in the 3′-untranslated region (3′-UTR) of BCL6. We further identified an inverse correlation between miR-10a levels and BCL6 protein levels, but not mRNA levels, in DLBCL tumor tissue samples. By overexpressing or knocking down miR-10a in DLBCL cells, we experimentally validated that miR-10a directly recognizes the 3′-UTR of the BCL6 transcript and regulated BCL6 expression. Furthermore, we demonstrated that negatively regulating BCL6 by miR-10a suppressed the proliferation and promoted apoptosis of DLBCL cells.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0316-z) contains supplementary material, which is available to authorized users.

Highlights

Worldwide, diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, accounting for 30%–40% of newly diagnosed non-Hodgkin lymphoma (NHL) cases (Yatomi, 2012)
The diffuse large B-cell lymphomas (DLBCL) and reactive lymph node hyperplasia (RLH) tissues were embedded in paraffin and stained with H&E or immunohistochemical staining of Bcl6 for histology examination (Fig. 1A)
After measuring the levels of BCL6 protein in DLBCL and RLH tissues via Western blotting, we found that BCL6 protein levels were significantly higher in the DLBCL tissues (Fig.1B, C)

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, accounting for 30%–40% of newly diagnosed non-Hodgkin lymphoma (NHL) cases (Yatomi, 2012). Recent studies have demonstrated that BCL6 plays an important role in the formation of germinal center (GC) B cells, which are the cells of origin of DLBCLs (Basso and Dalla-Favera, 2012; Ding et al, 2015). BCL6 is involved in the development of CD4+ T-follicular helper cells that play a critical role during the generation of germinal centers (Yu et al, 2009; Hollister et al, 2013). Most B cell lymphomas arise from GC B cells need continued expression of BCL6 to maintain their survival (Hatzi et al, 2013; Bertolo et al, 2013). Targeted inhibition of these BCL6 functions has emerged as the basis for the rational design of lymphoma therapies and combinatorial regimens

Methods

Results

Conclusion