Department of Burn and Plastic Surgery, Xi'an Ninth Hospital, Xi'an, Shaanxi 710054, China.
Department of Stomatology, Xi'an Ninth Hospital, Xi'an, Shaanxi 710054, China.
Biomed Pharmacother. 2018 Apr;100:184-190. doi: 10.1016/j.biopha.2018.01.158. Epub 2018 Feb 8.
MicroRNAs (miRNAs) play critical roles in various pathological processes, including hypertrophic scar (HS) formation. However, the precise role of miRNAs in HS formation remains largely unknown. In this study, we aimed to investigate the role of miR-519d in HS formation. We found that miR-519d expression was significantly downregulated in HS tissues and fibroblasts. Overexpression of miR-519d inhibited the expression of type I collagen (Col I), type III collagen (Col III) and α-smooth muscle actin (α-SMA) in HS fibroblasts. Moreover, overexpression of miR-519d reduced the proliferation and induced the apoptosis of HS fibroblasts. In contrast, suppression of miR-519d showed the opposite effects. Interestingly, Sirtuin 7 (SIRT7) was identified as a target gene of miR-519d. The results showed that miR-519d directly targeted the 3'-untranslated region of SIRT7 and negatively regulated its expression. Furthermore, miR-519d regulated the expression of TGF-β type I receptor (TGFBRI) and the phosphorylation of Smad2. Knockdown of SIRT7 by siRNA inhibited the expression of Col I, Col III and α-SMA, and reduced the proliferation and induced the apoptosis of HS fibroblasts. Overexpression of SIRT7 abrogated the effects mediated by miR-519d overexpression in HS fibroblasts. Overall, these results suggest that miR-519d inhibits the expression of extracellular matrix-associated genes, reduces the proliferation and induces the apoptosis of HS fibroblasts by targeting SIRT7, implying a suppressive role of miR-519d in HS formation. This study suggests that miR-519d may serve as a promising therapeutic target for treatment of human HS.
微小 RNA（miRNAs）在各种病理过程中发挥着关键作用，包括肥厚性瘢痕（HS）的形成。然而，miRNAs 在 HS 形成中的确切作用仍知之甚少。在这项研究中，我们旨在研究 miR-519d 在 HS 形成中的作用。我们发现 miR-519d 在 HS 组织和成纤维细胞中的表达显著下调。miR-519d 的过表达抑制了 HS 成纤维细胞中 I 型胶原（Col I）、III 型胶原（Col III）和 α-平滑肌肌动蛋白（α-SMA）的表达。此外，miR-519d 的过表达减少了 HS 成纤维细胞的增殖并诱导其凋亡。相反，抑制 miR-519d 则表现出相反的效果。有趣的是，Sirtuin 7（SIRT7）被鉴定为 miR-519d 的靶基因。结果表明，miR-519d 直接靶向 SIRT7 的 3'-非翻译区并负调控其表达。此外，miR-519d 调节 TGF-β Ⅰ型受体（TGFBRI）的表达和 Smad2 的磷酸化。siRNA 敲低 SIRT7 抑制了 Col I、Col III 和 α-SMA 的表达，并减少了 HS 成纤维细胞的增殖并诱导其凋亡。SIRT7 的过表达消除了 miR-519d 过表达在 HS 成纤维细胞中介导的作用。总之，这些结果表明，miR-519d 通过靶向 SIRT7 抑制细胞外基质相关基因的表达，减少 HS 成纤维细胞的增殖并诱导其凋亡，提示 miR-519d 在 HS 形成中具有抑制作用。这项研究表明，miR-519d 可能成为治疗人类 HS 的有前途的治疗靶点。
