Upregulation of Slug expression by cyclosporine A contributes to the pathogenesis of gingival overgrowth.
OBJECTIVE
Gingival overgrowth occurs as a side effect of systemic medication with immunosuppressant cyclosporine A (CsA). Slug, a master regulator of epithelial-mesenchymal transition, is dramatically upregulated in a variety of fibrotic diseases. The aim of this study is to investigate the role of epithelial-mesenchymal transition marker Slug in the pathogenesis of CsA-induced gingival overgrowth.


METHODS
Clinically healthy gingiva and CsA-induced gingival overgrowth specimens were analyzed by immunohistochemistry. The effect of CsA on normal human gingival fibroblasts (HGFs) was used to elucidate whether Slug expression could be affected by CsA by real-time reverse transcription-polymerase chain reaction and western blot. Cell proliferation in CsA-treated HGFs with Slug lentiviral-mediated shRNAi knockdown was evaluated by tetrazolium bromide reduction assay.


RESULTS
Slug expression was higher in CsA-induced gingival overgrowth specimens than in clinical healthy gingiva (p < 0.05). Slug expression was significantly higher in CsA-induced gingival overgrowth specimens with higher levels of inflammatory infiltrates (p < 0.05). CsA was found to increase Slug transcript and protein expression in HGFs in a dose-dependent manner (p < 0.05). In addition, knockdown of Slug significantly suppressed CsA-induced cell proliferation in HGFs (p < 0.05).


CONCLUSIONS
Taken together, upregulation of Slug in HGFs stimulated by CsA may play an important role in the pathogenesis of CsA-induced gingival overgrowth.
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Oral Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
Chung-Hung
CH
Tsai
Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan.
Cheng-Chia
CC
Yu
School of Public Health, Chung Shan Medical University, Taichung, Taiwan.
Shiuan-Shinn
SS
Lee
School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
Hui-Chieh
HC
Yu
School of Dentistry, Chung Shan Medical University, Taichung, Taiwan.
Fu-Mei
FM
Huang
School of Dentistry, Chung Shan Medical University, Taichung, Taiwan; Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan. Electronic address: cyc@csmu.edu.tw.
Yu-Chao
YC
Chang
D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005881:Gingiva / Q000473:pathology; D019214:Gingival Overgrowth / Q000139:chemically induced* / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D000071250:Snail Family Transcription Factors / Q000235:genetics*; D013624:Taiwan; D015854:Up-Regulation / Q000187:drug effects
D007166:Immunosuppressive Agents; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D016572:Cyclosporine
Slug; cyclosporine A; epithelial–mesenchymal transition; gingival overgrowth