Drug-induced gingival overgrowth (DIGO) is recognized as a side effect of nifedipine (NIF); however, the underlying molecular mechanisms remain unknown. In this study, we found that overexpressed miR-4651 inhibits cell proliferation and induces G0/G1-phase arrest in gingival mesenchymal stem cells (GMSCs) with or without NIF treatment. Furthermore, sequential window acquisition of all theoretical mass spectra (SWATH-MS) analysis, bioinformatics analysis, and dual-luciferase report assay results confirmed that high-mobility group AT-hook 2 (HMGA2) is the downstream target gene of miR-4651. Overexpression of HMGA2 enhanced GMSC proliferation and accelerated the cell cycle with or without NIF treatment. The present study demonstrates that miR-4651 inhibits the proliferation of GMSCs and arrests the cell cycle at the G0/G1 phase by upregulating cyclin D and CDK2 while downregulating cyclin E through inhibition of HMGA2 under NIF stimulation. These findings reveal a novel mechanism regulating DIGO progression and suggest the potential of miR-4651 and HMGA2 as therapeutic targets.

中文翻译：

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miR-4651在硝苯地平治疗下通过抑制HMGA2抑制牙龈间充质干细胞的细胞增殖。

药物引起的牙龈过度生长（DIGO）被认为是硝苯地平（NIF）的副作用；然而，潜在的分子机制仍然未知。在这项研究中，我们发现过度表达的miR-4651抑制或不进行NIF治疗的牙龈间充质干细胞（GMSC）中的细胞增殖并诱导G0 / G1期阻滞。此外，所有理论质谱（SWATH-MS）分析，生物信息学分析和双荧光素酶报告测定结果的顺序窗口采集证实，高迁移率的AT-hook 2组（HMGA2）是miR-4651的下游靶基因。HMGA2的过表达增强了GMSC的增殖，并在有或没有NIF处理的情况下加速了细胞周期。本研究表明，miR-4651通过上调细胞周期蛋白D和CDK2抑制GMSCs的增殖，并在G0 / G1期阻止细胞周期，而在NIF刺激下通过抑制HMGA2下调细胞周期蛋白E。这些发现揭示了调节DIGO进展的新机制，并暗示了miR-4651和HMGA2作为治疗靶标的潜力。