Abstract
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.
Highlights
Drug-induced gingival overgrowth (DIGO) is a tissue-specific oral disease that involves hyperplasia and hypertrophy of the gingiva.DIGO is an adverse drug reaction related largely to three types of medicines: antiepileptic drugs, immunosuppressants and calcium channel blockers (CCBs).[1,2,3] Gingival overgrowth is a major problem in maintaining oral hygiene, increasing the patient’s vulnerability to oral infection, inflammation and periodontal disease
Our research showed that miR-3940-5p inhibits the proliferation of gingival mesenchymal stem cells (GMSCs), Overexpression of HMGA2 promotes cell proliferation and cell arresting the cell cycle at the G0/G1 phase
Our findings revealed that and augmented the percentage in S and G2/M phases in GMSCs miR-4651 inhibits the proliferation of GMSCs by targeting HMGA2. compared with the control group, regardless of whether the cells were treated with 1 μg·mL−1 NIF (Fig. 6a, b)
Summary
Index data revealed that HMGA2 overexpression promoted the proliferation of GMSCs with or without 1 μg·mL−1 NIF. CFSE results showed that overexpression of HMGA2 upregulated the protein the miR-4651 mimic inhibited the growth of GMSCs, even when treated with 1 μg·mL−1 NIF (Fig. 2b, c). Mediated inhibition of proliferation was related to cell cycle levels of p15INK4b, cyclin A, and cyclin E and downregulated the levels of cyclin D and CDK2 compared with the control group under treatment with 1 μg·mL−1 NIF (Fig. 7b). Real-time RT-PCR results indicated that overexpressed miR-4651 significantly repressed HMGA2 expression at the mRNA level (Fig. 4b). Cells in the body are maintained by cell cycle regulation, which controls cell proliferation.[45] Cell cycle arrest can be caused by multiple stimulators, which may lead to cell division inhibition, cell death, and/or apoptosis.[46] Our study revealed that miR-4651 had inhibitory effects on GMSC cell growth by inducing significant G0/.
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