Long noncoding RNA DNM3OS promotes prostate stromal cells transformation via the miR-29a/29b/COL3A1 and miR-361/TGFβ1 axes.

Ruizhe Wang,Lingxiao Chen,Mengda Zhang,Lin Qi,Zhenyu Ou,Long Wang,Shusuan Jiang,Ran Xu,Yao He,Wei He,Junjie Zhang

doi:10.18632/aging.102395

Abstract

Transforming growth factor-β1 (TGFβ1)-induced differentiation into and the activation of myofibroblasts have been regarded as critical events in benign prostatic hyperplasia (BPH); however, the underlying mechanisms of BPH pathogenesis remain unclear. Microarray profiling, STRING analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation, and Gene Ontology (GO) enrichment analysis were performed to confirm the candidate genes and long non-coding RNA (lncRNAs) related to BPH. Collagen Type III (COL3A1) was significantly upregulated by TGFβ1 in prostate stromal cells (PrSCs) and might be involved in DNM3OS function in myofibroblasts upon TGFβ1 stimulation. Upon TGFβ1 stimulation, COL3A1 protein was decreased by DNM3OS silencing. miR-29a and miR-29b could directly bind to the DNM3OS and COL3A1 3' untranslated region (UTR)s to negatively regulate their expression, and by serving as a competing endogenous RNAs (ceRNA), DNM3OS competed with COL3A1 for miR-29a/29b binding, therefore counteracting miR-29a/29b-mediated COL3A1 suppression. The effect of DNM3OS silencing on ECM components and TGFβ1 downstream signaling was similar to that of the TGFβ1 inhibitor SB431542. miR-361 could target DNM3OS and TGFβ1; DNM3OS competed for miR-361 binding to counteract miR-361-mediated TGFβ1 suppression. In conclusion, we identified DNM3OS as a specifically-upregulated lncRNA upon TGFβ1 stimulation in PrSCs; by serving as a ceRNA for the miR-29a/29b cluster and miR-361, DNM3OS eliminated miRNA-mediated suppression of COL3A1 and TGFβ1, thereby promoting TGFβ1-induced PrSC transformation into myofibroblasts.

Highlights

Benign prostatic hyperplasia (BPH), one of most commonly seen diseases of the urinary system, has an incidence of up to 60% in men aged between 40 and 60 years and higher than 90% in men aged 80 and over [1, 2]
Chronic inflammation is related to the initiation and/or development of tissue fibrosis, which is characterized by increased number and activity of myofibroblasts, collagen deposition and remodeling of extracellular matrix (ECM) [10]
Selection of long noncoding RNA (lncRNA) associated with benign prostatic hyperplasia (BPH) stroma and highlyexpressed in prostate stromal tissues

Summary

Introduction

Benign prostatic hyperplasia (BPH), one of most commonly seen diseases of the urinary system, has an incidence of up to 60% in men aged between 40 and 60 years and higher than 90% in men aged 80 and over [1, 2]. Produced by stromal cells, transforming growth factorβ (TGFβ1) is a direct predisposing factor for prostate stromal hyperplasia, which is involved in multiple processes during the development of BPH, including inflammation. During the differentiation of fibroblasts to myofibroblasts, several changes in gene expression have been regarded as a signature of myofibroblasts, such as increased expression of Tnc, Lox, ELN, COL3A1, and Tnfrsf12a [11, 12] Consistent with these observations, TGFβ1 is one of the critical cytokines that induce fibroblasts to transform into myofibroblasts and promote fibrosis, during which the expression of COL1A1, COL3A1, and α-SMA is increased [13, 14]. The fibrosis process in the liver and kidney can be affected by multiple factors including growth factors, which induce cell differentiation into myofibroblasts [15, 16]. We speculate that the differentiation into and the activation of myofibroblasts play a critical role in BPH pathogenesis

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Results

Conclusion