Hypertrophic scar (HS) formation is associated with the fibrosis of fibrocytes which is caused by excessive extracellular matrix (ECM) synthesis and deposition. A recent high throughput screen of miRNA expression profiles using miRNA microarray technology identified hsa-miR31-5p was most differentially expressed in normal skin fibroblasts (NS) and HS.

The level of hsa-miR31-5p in HS was significantly higher than in NS. In-vitro functional experiments showed hsa-miR31-5p knockdown remarkably suppressed the proliferation of hypertrophic scar fibroblasts (HSFBs) under hypoxia, promoted cell invasion, and inhibited the expression of Collagen I and III and Fibronectin (FN), suggesting hsa-miR31-5p knockdown effectively reduces HS formation caused by excessive ECM synthesis and deposition in HSFBs under hypoxia. Mechanism study showed the regulation of HS formation by hsa-miR31-5p was mediated by its target gene, factor-inhibiting HIF-1 (FIH): under hypoxia, hsa-miR31-5p down-regulated FIH and thus increased the level of hypoxia inducible factor-1α (HIF-1α). This subsequently activated the HIF-1α fibrosis regulation pathway in HSFBs and stimulated ECM synthesis in HSFBs, eventually resulting in fibrosis and scar formation. The data also show that knockdown of hsa-miR31-5p in HSFBs impaired the trend of increased proliferation, reduced invasion and excessive ECM synthesis and deposition caused by HIF-1a activation under hypoxia through upregulating FIH. This indicates that knockdown of hsa-miR31-5p effectively inhibits the formation of HS.

In conclusion, hsa-miR31 -5p plays an important role in HS formation by inhibiting FIH and regulating the HIF-1α pathway. Therefore, hsa-miR31 -5p may be a novel therapeutic target for HS.

 

Efficiency of lentiviral infection and expression of hsa-miR31-5p and FIH protein in HSFBs infected. (A) HSFBs were infected with Lv-NC and GFP was observed under fluorescence microscopy 72 h later. (B) HSFBs were infected with Lv-NC or Lv-sponge-miR31-5p or Lv-shRNA-FIH. Then the hsa-miR31-5p (right) and FIH (left) levels were assessed by quantitative PCR or Western blotting. Data are expressed as mean ± SD of at least three independent experiments. **, P < 0.01 *, P < 0.05, when compared to cell control or NC groups. Representative blots are shown.

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Reference
X. Wang, Y. Zhang, B.H. Jiang, Q. Zhang, R.P. Zhou, L. Zhang, C. Wang (2017) Study on the role of Hsa-miR-31-5p in hypertrophic scar formation and the mechanism Exp. Cell Res. doi: 10.1016/j.yexcr.2017.09.009 [abstract]

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