Long noncoding RNA DNM3OS promotes prostate stromal cells transformation via the miR-29a/29b/COL3A1 and miR-361/TGFβ1 axes
Long noncoding RNA DNM3OS promotes prostate stromal cells transformation via the miR-29a/29b/COL3A1 and miR-361/TGFβ1 axes
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长非编码RNA DNM3OS通过miR-29a/29b/COL3A1和miR-361/TGF beta 1轴促进前列腺基质细胞转化
DOI：
10.18632/aging.102395
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发表时间：
2019-11-15
期刊：
影响因子：
5.2
通讯作者：
Wang, Long
中科院分区：
文献类型：
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作者：
Wang, Ruizhe;Zhang, Mengda;Wang, Long
转化生长因子β 1（TGF β 1）诱导的肌成纤维细胞分化和活化被认为是良性前列腺增生（BPH）的关键事件;然而，BPH发病机制的潜在机制仍不清楚。通过微阵列分析、STRING分析、京都基因和基因组百科全书（KEGG）途径注释和基因本体（GO）富集分析来确认与BPH相关的候选基因和长链非编码RNA（lncRNA）。前列腺基质细胞（PrSC）中的TGF β 1显著上调III型胶原（COL3A1），并可能参与TGF β 1刺激后肌成纤维细胞中的DNM3OS功能。在TGF β 1刺激后，COL3A1蛋白通过DNM3OS沉默而降低。miR-29 a和miR-29 b可直接与DNM3OS和COL3A1的3 '非翻译区（UTR）结合，负调控其表达，DNM3OS作为竞争性内源RNA（ceRNA）与COL3A1竞争miR-29 a/29 b结合，从而抵消miR-29 a/29 b介导的COL3A1抑制作用。DNM30S沉默对ECM组分和TGF β 1下游信号传导的作用与TGF β 1抑制剂SB 431542的作用相似。miR-361可以靶向DNM3OS和TGF β 1; DNM3OS竞争miR-361结合以抵消miR-361介导的TGF β 1抑制。总之，我们将DNM3OS鉴定为PrSC中TGF β 1刺激后特异性上调的lncRNA;通过充当miR-29 a/29 b簇和miR-361的ceRNA，DNM3OS消除了miRNA介导的COL3A1和TGF β 1的抑制，从而促进TGF β 1诱导的PrSC转化为肌成纤维细胞。
Transforming growth factor-beta 1 (TGF beta 1)-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 TGF beta 1 in prostate stromal cells (PrSCs) and might be involved in DNM3OS function in myofibroblasts upon TGF beta 1 stimulation. Upon TGF beta 1 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 TGF beta 1 downstream signaling was similar to that of the TGF beta 1 inhibitor SB431542. miR-361 could target DNM3OS and TGF beta 1; DNM3OS competed for miR-361 binding to counteract miR-361-mediated TGF beta 1 suppression. In conclusion, we identified DNM3OS as a specifically-upregulated lncRNA upon TGF beta 1 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 TGF beta 1, thereby promoting TGF beta 1-induced PrSC transformation into myofibroblasts.