MiR-449a inhibits cell proliferation, migration, and inflammation by regulating high-mobility group box protein 1 and forms a mutual inhibition loop with Yin Yang 1 in rheumatoid arthritis fibroblast-like synoviocytes

Yongsong Cai,Peng Xu,Xiaoyu Ren,Congshan Jiang,Ke Xu,Bo Wang,Lin Xu,Peijing Hu,Qiling Yuan,Jialin Zhu,Yusheng Qiu,Yuanxu Guo,Jian Sun

doi:10.1186/s13075-019-1920-0

Abstract

BackgroundWe previously found that high-mobility group box protein 1 (HMGB1) promoted cell proliferation, migration, invasion, and autophagy in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), but little is known about its regulatory mechanism. The aim of this study was to investigate the regulatory mechanism of HMGB1 at the posttranscription level.MethodsReal-time qPCR, CCK-8 cell proliferation assay, transwell cell migration assay, enzyme-linked immunosorbent assay (ELISA), and western blotting were used in this study. The targeting relationship between miRNA and mRNA was presented by the luciferase reporter assay.ResultsMiR-449a was downregulated in RA synovial tissue and inhibited RA-FLS proliferation, migration, and IL-6 production. MiR-449a directly targeted HMGB1 and inhibited its expression. Yin Yang 1(YY1) negatively regulated miR-449a expression and formed a mutual inhibition loop in RA-FLS. MiR-449a inhibited TNFα-mediated HMGB1 and YY1 overexpression and IL-6 production.ConclusionsOur results reveal the regulatory mechanism of HMGB1 in RA and demonstrate that miR-449a is a crucial molecule in RA pathogenesis and a suitable candidate for miRNA replacement therapies in RA.

Highlights

We previously found that high-mobility group box protein 1 (HMGB1) promoted cell proliferation, migration, invasion, and autophagy in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), but little is known about its regulatory mechanism
We further found that miR-449a inhibited TNFα-mediated HMGB1 and Yin Yang1 (YY1) overexpression and IL-6 production. miR-449a may be a crucial molecule in Rheumatoid arthritis (RA) pathogenesis and a suitable candidate for miRNA replacement therapies in RA
MiR-449a inhibits cell proliferation, migration, and inflammation in RA-FLS The quantitative PCR results indicated that miR449a expression was significantly downregulated both in RA synovial tissue and RA-FLS compared with OA (Fig. 1a, b)

Summary

Introduction

We previously found that high-mobility group box protein 1 (HMGB1) promoted cell proliferation, migration, invasion, and autophagy in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), but little is known about its regulatory mechanism. Studies have found that microRNAs (miRNAs) control various cellular processes and play an important role in different diseases, including RA [4, 5]. Several miRNAs were observed to be abnormally expressed in RA, and some of which affected RA-FLS cell proliferation, inflammation, or cellular signaling pathways [6,7,8]. MiR-449a, located on chromosome 5q11, has been reported to be dysregulated in some diseases and influences cell apoptosis, proliferation, invasion, migration, and inflammation by regulating the expression of various genes [9,10,11,12,13,14]. Little is known about the function of miR-449a in RA

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