Background Hypertrophic scar (HS) is a common fibroproliferative skin disease that currently has no truly effective therapy. Given the importance of phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) in hypertrophic scar formation, the development of therapeutic strategies for endogenous inhibitors against PIK3CA is of great interest. Here, we explored the molecular mechanisms underlying the protective effects of miR-203a-3p (PIK3CA inhibitor) against excessive scar. Methods Bioinformatic analysis, immunohistochemistry, immunofluorescence, miRNA screening and fluorescence in situ hybridization assays were used to identify the possible pathways and target molecules mediating HS formation. A series of in vitro and in vivo experiments were used to clarify the role of PIK3CA and miR-203a-3p in HS. Mechanistically, transcriptomic sequencing, immunoblotting, dual-luciferase assay and rescue experiments were executed. Results Herein, we found that PIK3CA and the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway were upregulated in scar tissues and positively correlated with fibrosis. We then identified miR-203a-3p as the most suitable endogenous inhibitor of PIK3CA. miR-203a-3p suppressed the proliferation, migration, collagen synthesis and contractility as well as the transdifferentiation of fibroblasts into myofibroblasts in vitro, and improved the morphology and histology of scars in vivo. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating the PI3K/AKT/mTOR pathway by directly targeting PIK3CA. Conclusions PIK3CA and the PI3K/AKT/mTOR pathway are actively involved in scar fibrosis and miR-203a-3p might serve as a potential strategy for hypertrophic scar therapy through targeting PIK3CA and inactivating the PI3K/AKT/mTOR pathway.

中文翻译：

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miR-203a-3p 对磷脂酰肌醇 3-激酶催化亚基 α 的抑制可通过磷脂酰肌醇 3-激酶/AKT/mTOR 信号通路减少肥厚性疤痕形成

背景 肥厚性疤痕（HS）是一种常见的纤维增生性皮肤病，目前尚无真正有效的治疗方法。鉴于磷脂酰肌醇 3-激酶催化亚基 α (PIK3CA) 在肥厚性疤痕形成中的重要性，针对 PIK3CA 的内源性抑制剂的治疗策略的开发引起了人们的极大兴趣。在这里，我们探讨了 miR-203a-3p（PIK3CA 抑制剂）对过度疤痕的保护作用的分子机制。方法采用生物信息学分析、免疫组化、免疫荧光、miRNA筛选和荧光原位杂交检测来鉴定介导HS形成的可能途径和靶分子。通过一系列体外和体内实验阐明 PIK3CA 和 miR-203a-3p 在 HS 中的作用。从机制上讲，进行了转录组测序、免疫印迹、双荧光素酶测定和救援实验。结果本文中，我们发现 PIK3CA 和磷脂酰肌醇 3 激酶 (PI3K)/AKT/mTOR 通路在疤痕组织中上调，并与纤维化呈正相关。然后我们确定 miR-203a-3p 是最合适的 PIK3CA 内源抑制剂。miR-203a-3p在体外抑制成纤维细胞的增殖、迁移、胶原合成和收缩性以及向肌成纤维细胞的转分化，并在体内改善疤痕的形态和组织学。从机制上讲，miR-203a-3p 通过直接靶向 PIK3CA 灭活 PI3K/AKT/mTOR 通路来减轻纤维化。结论 PIK3CA 和 PI3K/AKT/mTOR 通路积极参与疤痕纤维化，miR-203a-3p 可能通过靶向 PIK3CA 和灭活 PI3K/AKT/mTOR 通路作为增生性疤痕治疗的潜在策略。