MicroRNA-181a Inhibits Activated B-Cell-Like Diffuse Large B-Cell Lymphoma Progression by Repressing CARD11.

Danxia Zhu,Wenting He,Chen Wu,Jun Wu,Xiaodong Li,Cheng Fang

doi:10.1155/2019/9832956

Danxia Zhu, Wenting He + Show 4 more

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https://doi.org/10.1155/2019/9832956

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Abstract

We investigated the role of miR-181a in diffuse large B-cell lymphoma (DLBCL) and its potential target genes. miR-181a levels were lower in activated B-cell- (ABC-) like DLBCL cells than that in germinal center B-cell- (GCB-) like DLBCL cells. Overexpression of miR-181a in ABC-like DLBCL cell lines (OCI-LY10 and U2932) resulted in G0/G1 cell cycle arrest, increased apoptosis, and decreased invasiveness. miRNA target prediction programs (miRanda, TargetScan, and miRDB) identified caspase recruitment domain-containing protein 11 (CARD11) as a putative miR-181a target. CARD11 mRNA and protein levels were higher in the ABC-like DLBCL than that in GCB-like DLBCL. Moreover, CARD11 mRNA and protein levels were downregulated in the OCI-LY10 and U2932 cell lines overexpressing miR-181a. Dual luciferase reporter assays confirmed the miR-181a binding site in the CARD11 3′UTR region. OCI-LY10 and U2932 cells transfected with a CARD11 expression vector encoding miR-181a with a mutated binding site showed higher CARD11 protein levels, cell viability, G2/M phase cells, and invasiveness compared to those transfected with a wild-type CARD11 expression vector. Nude mice xenografted with OCI-LY10 cells with overexpressed wild-type miR-181a generated smaller tumors compared to those with overexpressed mutated binding site of CARD11 3′UTR and miR-181a. These results indicate that miR-181a inhibits ABC-like DLBCL by repressing CARD11.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoma that is highly heterogeneous
MiR-181b levels were similar between germinal center B-cell (GCB)- and activated B-cell- (ABC-)like DLBCL cell lines. is suggested that miR-181a expression may be associated with the differential development of the different DLBCL subgroups
Based on gene expression profiling and tumor cell origins, DLBCL is classified into germinal center B-cell (GCB) type and activated B-cell (ABC) type [12, 13]. e proportion of the ABC type is higher in Chinese patients than that in western countries and accounts for 70%–80% of DLBCL cases [14]

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is a malignant lymphoma that is highly heterogeneous. Ey regulate cell differentiation, proliferation, apoptosis, and other basic cellular processes and play an important role in tumor diagnosis and prognosis [3, 4]. E miR181 family is involved in immune regulation, angiogenesis, tumor resistance to chemotherapy, and prognosis evaluation [5,6,7,8]. MiR-181a/b suppresses the malignant transformation of B-lymphocytes by inhibiting cytidine deaminase (AID), BCL-6, FOXP-1, and other key genes that are involved in malignant transformation and differentiation of B-cells [5, 9, 10]. We analyzed 866 human miRNAs in six Chinese patients with chronic lymphocytic leukemia (CLL) and peripheral B-cells from pooled 30 healthy donors [11]. We investigated the role of miR-181a/b in DLBCL and its target genes that are relevant for tumor growth and progression

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