Jin Mingzhu, Xu Xiao
Department of Burns and Plastic Surgery, Fourth Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China.
Department of Ophthalmology, Third Medical Center of Chinese PLA General Hospital, Beijing, People's Republic of China.
Clin Cosmet Investig Dermatol. 2023 Mar 8;16:565-580. doi: 10.2147/CCID.S397808. eCollection 2023.
Secondary to war wounds, trauma, etc., hypertrophic scar formation is the cause of an excessive proliferation of fibroblasts and accumulation of collagen fibers, which might affect cosmetic appearance, and could cause malignant transformation. miRNAs play an important role in disease regulation via inhibiting post-transcriptional protein translation by targeting and binding to the 3' UTR region of mRNA. Here we explore the mechanism and interventions of scar formation from the perspective of miRNA.
Hypertrophic scar-associated differential miRNAs were screened by analyzing sequencing data of normal skin and hypertrophic scar, and verified by RT-qPCR. Signaling pathways that may be influenced by differentially miRNAs were analyzed using KEGG and GO. miRNA mimics were used to explore the effects of miRNAs on SMAD signaling pathway proteins. Dual-luciferase assays were used to explore the targeted binding of miRNAs. The mimics of the miRNA were used to explore the impact of miRNAs on the proliferation, migration, apoptosis and collagen synthesis levels of hypertrophic scar fibroblasts. The scar model of rabbit ear was used to verify the influence of miRNA on wound healing and scar formation in vivo.
Expression of miR-182-5p was found to be considerably decreased in hypertrophic scars and fibroblasts. miR-182-5p was found to act mainly by targeting the 3'UTR region of SMAD4, but not SMAD1 or SMAD3. miR-182-5p overexpression may drastically suppress the proliferation and migration of fibroblasts, accompanied by enhanced apoptosis and reduced collagen fiber synthesis. The overexpression of miR-182-5p in in vivo experiments could effectively inhibit hypertrophic scar formation without affecting the speed and quality of wound healing.
miR-182-5p inhibits hypertrophic scar formation by decreasing the proliferation and migration of fibroblasts via SMAD4 pathway, and is expected to become a novel hypertrophic scar therapeutic target.
继发于战争创伤、外伤等，增生性瘢痕形成是成纤维细胞过度增殖和胶原纤维堆积的结果，这可能影响外观，并可能导致恶性转化。微小RNA（miRNA）通过靶向并结合mRNA的3'非翻译区（UTR）抑制转录后蛋白质翻译，在疾病调控中发挥重要作用。在此，我们从miRNA的角度探讨瘢痕形成的机制及干预措施。
通过分析正常皮肤和增生性瘢痕的测序数据筛选出与增生性瘢痕相关的差异miRNA，并通过逆转录定量聚合酶链反应（RT-qPCR）进行验证。使用京都基因与基因组百科全书（KEGG）和基因本体论（GO）分析可能受差异miRNA影响的信号通路。使用miRNA模拟物探讨miRNA对SMAD信号通路蛋白的影响。采用双荧光素酶测定法探讨miRNA的靶向结合。使用miRNA模拟物探讨miRNA对增生性瘢痕成纤维细胞增殖、迁移、凋亡和胶原合成水平的影响。采用兔耳瘢痕模型验证miRNA对体内伤口愈合和瘢痕形成的影响。
发现miR-182-5p在增生性瘢痕和成纤维细胞中的表达显著降低。发现miR-182-5p主要通过靶向SMAD4的3'UTR区域发挥作用，而不是SMAD1或SMAD3。miR-182-5p过表达可能显著抑制成纤维细胞的增殖和迁移，同时伴随凋亡增加和胶原纤维合成减少。在体内实验中，miR-182-5p的过表达可有效抑制增生性瘢痕形成，而不影响伤口愈合的速度和质量。
miR-182-5p通过SMAD4途径降低成纤维细胞的增殖和迁移来抑制增生性瘢痕形成，有望成为新型增生性瘢痕治疗靶点。
