Knockdown of lncRNA-ATB suppresses autocrine secretion of TGF-β2 by targeting ZNF217 via miR-200c in keloid fibroblasts.
Knockdown of lncRNA-ATB suppresses autocrine secretion of TGF-β2 by targeting ZNF217 via miR-200c in keloid fibroblasts.
复制标题
IncRNA-ATB 的敲低通过 miR-200c 靶向 ZNF217 抑制瘢痕疙瘩成纤维细胞中 TGF-β 2 的自分泌分泌
DOI：
10.1038/srep24728
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发表时间：
2016-04-19
影响因子：
4.6
通讯作者：
Hu DH
中科院分区：
文献类型：
--
作者：
Zhu HY;Bai WD;Li C;Zheng Z;Guan H;Liu JQ;Yang XK;Han SC;Gao JX;Wang HT;Hu DH
转化生长因子-β (TGF-β)信号的异常高激活已被证明参与瘢痕疙瘩的发生和发展。然而，TGF-β激活的长链非编码RNA （lncRNA- atb）在瘢痕疙瘩中的功能作用尚未被证实。本文研究lncRNA-ATB在瘢痕疙瘩成纤维细胞（KFs）自分泌TGF-β中的作用，并探讨其潜在的分子机制。通过免疫组织化学和定量RT-PCR分析，我们发现lncRNA-ATB和TGF-β转录激活因子ZNF217在瘢痕疙瘩组织和瘢痕疙瘩成纤维细胞中过表达，而靶向ZNF217的miR-200c低表达。通过功能获得和功能丧失研究，我们证明lncRNA-ATB的下调降低了TGF-β2的自分泌和ZNF217的表达，但上调了KFs中miR-200c的表达。稳定下调ZNF217表达可降低TGF-β2的自分泌。miR-200c内源性与lncRNA-ATB相关，抑制miR-200c克服了KFs中ZNF217表达的减少。综上所述，这些发现表明，lncRNA-ATB通过miR-200c下调ZNF217的表达水平，至少在一定程度上调控了KFs中TGF-β2的自分泌，提示lncRNA-ATB/miR-200c/ZNF217/TGF-β2信号轴。这些发现可能为瘢痕疙瘩的新诊断和治疗方法提供潜在的生物标志物和靶点。
Abnormally high activation of transforming growth factor-β (TGF-β) signaling has been demonstrated to be involved in the initiation and progression of keloids. However, the functional role of long non-coding RNA (lncRNA)-activated by TGF-β (lncRNA-ATB) in keloids has not been documented. Here we investigated the role of lncRNA-ATB in the autocrine secretion of TGF-β in keloid fibroblasts (KFs) and explored the underlying molecular mechanism. Using immunohistochemistry and quantitative RT-PCR analysis, we showed that lncRNA-ATB and ZNF217, a transcriptional activator of TGF-β, were overexpressed and miR-200c, which targets ZNF217, was under-expressed in keloid tissue and keloid fibroblasts. Through gain- and loss-of-function studies, we demonstrated that knockdown of lncRNA-ATB decreased autocrine secretion of TGF-β2 and ZNF217 expression but upregulated expression of miR-200c in KFs. Stable downregulation of ZNF217 expression decreased the autocrine secretion of TGF-β2. miR-200c was endogenously associated with lncRNA-ATB, and inhibition of miR-200c overcame the decrease in ZNF217 expression in KFs. Taken together, these findings indicate that lncRNA-ATB governs the autocrine secretion of TGF-β2 in KFs, at least in part, by downregulating the expression level of ZNF217 via miR-200c, suggesting a signaling axis consisting of lncRNA-ATB/miR-200c/ZNF217/TGF-β2. These findings may provide potential biomarkers and targets for novel diagnostic and therapeutic approaches for keloids.