Inhibition of phosphatidylinositol 3-kinase catalytic subunit alpha by miR-203a-3p reduces hypertrophic scar formation via phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway

• Published in: Burns and trauma Vol. 12; p. tkad048
• Main Authors: Zhao, Shixin, Liu, Hengdeng, Wang, Hanwen, He, Xuefeng, Tang, Jinming, Qi, Shaohai, Yang, Ronghua, Xie, Julin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-01-2024
• Subjects: Transdifferentiation; Fibrosis; mTOR; miRNA; AKT; Hypertrophic scar; Phosphatidylinositol 3-kinase; miR-203a-3p; Phosphatidylinositol 3-kinase catalytic subunit alpha
• ISSN: 2321-3868; 2321-3876; 2321-3876
• DOI: 10.1093/burnst/tkad048

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.
Bioinformatic analysis, immunohistochemistry, immunofluorescence, miRNA screening and fluorescence
hybridization assays were used to identify the possible pathways and target molecules mediating HS formation. A series of
and
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.
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
, and improved the morphology and histology of scars
. Mechanistically, miR-203a-3p attenuated fibrosis by inactivating the PI3K/AKT/mTOR pathway by directly targeting PIK3CA.
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.