miR-141 regulates TGF-β1-induced epithelial-mesenchymal transition through repression of HIPK2 expression in renal tubular epithelial cells.
miR-141 regulates TGF-β1-induced epithelial-mesenchymal transition through repression of HIPK2 expression in renal tubular epithelial cells.
复制标题
DOI：
10.3892/ijmm.2014.2008
复制
发表时间：
2015-02
影响因子：
5.4
通讯作者：
Chen Z
中科院分区：
文献类型：
--
作者：
Huang Y;Tong J;He F;Yu X;Fan L;Hu J;Tan J;Chen Z
上皮-间质转化（EMT）在胚胎发育、伤口愈合、组织再生、癌症进展和器官纤维化中起关键作用。近端肾小管上皮细胞经历EMT，导致基质产生成纤维细胞，从而促成肾纤维化的发病机制。促纤维化细胞因子TGF-β现在被认为是已显示在肾小管上皮细胞中诱导EMT的主要致病驱动因素。越来越多的证据表明，HIPK 2功能障碍可能在成纤维细胞行为中起作用，因此，HIPK 2可能被认为是抗纤维化治疗的新的潜在靶点。最近，miR-200家族的成员（miR-200 a、B和c以及miR-141）已显示出抑制EMT。然而，这些miRNAs，特别是miR-141，调节多因素肾纤维化进展的步骤尚不清楚。为了研究miR-141在EMT中的功能重要性，使用成熟的体外EMT测定来证明肾小管间质纤维化;转化生长因子-β1诱导HK-2细胞中的EMT。miR-141在HK-2细胞中的过表达，无论是否有TGF-β1处理，都通过增强E-cadherin和降低vimentin和成纤维细胞特异性蛋白1的表达来阻碍EMT。miR-141的表达在EMT期间通过HIPK 2表达的上调以剂量和时间依赖性方式受到抑制。HIPK 2的异位表达通过减少E-cadherin促进EMT。此外，miR-141与HIPK 2 ORF克隆的共转染通过恢复E-cadherin表达而部分抑制EMT。miR-141通过与HIPK 2的3′-非翻译区直接相互作用下调HIPK 2的表达。综上所述，这些发现有助于理解miR-141通过TGF-β1/miR-141/HIPK 2/EMT轴调节肾纤维化的作用和机制，miR-141可能代表治疗肾纤维化的新生物标志物和治疗靶点。
Epithelial-mesenchymal transition (EMT) plays a critical role in embryonic development, wound healing, tissue regeneration, cancer progression and organ fibrosis. The proximal tubular epithelial cells undergo EMT, resulting in matrix-producing fibroblasts and thereby contribute to the pathogenesis of renal fibrosis. The profibrotic cytokine, TGF-β, is now recognized as the main pathogenic driver that has been shown to induce EMT in tubular epithelial cells. Increasing evidence indicate that HIPK2 dysfunction may play a role in fibroblasts behavior, and therefore, HIPK2 may be considered as a novel potential target for anti-fibrosis therapy. Recently, members of the miR-200 family (miR-200a, b and c and miR-141) have been shown to inhibit EMT. However, the steps of the multifactorial renal fibrosis progression that these miRNAs regulate, particularly miR-141, are unclear. To study the functional importance of miR-141 in EMT, a well-established in vitro EMT assay was used to demonstrate renal tubulointerstitial fibrosis; transforming growth factor-β1-induced EMT in HK-2 cells. Overexpression of miR-141 in HK-2 cells, either with or without TGF-β1 treatment, hindered EMT by enhancing E-cadherin and decreasing vimentin and fibroblast-specific protein 1 expression. miR-141 expression was repressed during EMT in a dose- and time-dependent manner through upregulation of HIPK2 expression. Ectopic expression of HIPK2 promoted EMT by decreasing E-cadherin. Furthermore, co-transfection of miR-141 with the HIPK2 ORF clone partially inhibited EMT by restoring E-cadherin expression. miR-141 downregulated the expression of HIPK2 via direct interaction with the 3′-untranslated region of HIPK2. Taken together, these findings aid in the understanding of the role and mechanism of miR-141 in regulating renal fibrosis via the TGF-β1/miR-141/HIPK2/EMT axis, and miR-141 may represent novel biomarkers and therapeutic targets in the treatment of renal fibrosis.
登录
查看更多内容
影响因子：
5.6
作者：
Ricci, Alberto;Cherubini, Emanuela;Mariotta, Salvatore
通讯作者：
Mariotta, Salvatore
影响因子：
3.2
作者：
Patel V;Noureddine L
通讯作者：
Noureddine L
影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1083/jcb.130.2.393
发表时间：
1995-07
期刊：
The Journal of cell biology
影响因子：
--
作者：
Strutz F;Okada H;Lo CW;Danoff T;Carone RL;Tomaszewski JE;Neilson EG
通讯作者：
Neilson EG
影响因子：
9.2
作者：
Lan HY
通讯作者：
Lan HY