MicroRNA let-7a mitigates the progression of oral submucous fibrosis by targeting high-mobility group AT-hook 2

Oral submucous fibrosis (OSF) is an irreversible fibrotic disorder of the oral cavity with a high potential for malignant transformation. MicroRNA lethal-7a (let-7a) has been recognized as a key antifibrotic regulator, but its specific role in OSF remains unknown. Therefore, this study aimed to elucidate the functional significance and the molecular mechanism of let-7a in OSF progression.

The expression of let-7a was quantified by real-time quantitative polymerase chain reaction in fibrotic buccal mucosal fibroblasts (fBMFs) isolated from OSF lesions and patient-matched non-fibrotic BMFs (BMFs). Myofibroblastic characteristics were evaluated using collagen-gel contraction, Transwell migration, and wound-healing assays. Restoration and inhibition of let-7a expression were achieved by transfecting let-7a mimics or inhibitors, respectively. Direct binding of let-7a to high-mobility group AT-hook 2 (HMGA2) mRNA was verified using luciferase reporter assay.

Let-7a expression was significantly down-regulated in fBMFs isolated from OSF lesions compared with patient-matched non-fibrotic BMFs. Moreover, let-7a expression declined in a dose-dependent manner during arecoline-induced myofibroblastic transdifferentiation of BMFs. Myofibroblastic characteristics, including cell contractility, cell migration, and wound-healing capacity were significantly decreased in fBMFs after transfection of let-7a mimics. Mechanistically, let-7a directly targeted the HMGA2 mRNA, leading to post-transcriptional repression of HMGA2. Importantly, silencing of HMGA2 was sufficient to diminish cell contractility and myofibroblasts marker expression in fBMFs.

The present study demonstrates that let-7a suppresses oral myofibroblast activation by directly targeting HMGA2. This finding first establishes the let-7a/HMGA2 axis as a promising therapeutic target for mitigating the progression of OSF.