Abstract
BackgroundArecoline is an alkaloid natural product found in the areca nut that can induce oral submucous fibrosis and subsequent development of cancer. However, numerous studies have shown that arecoline may inhibit fibroblast proliferation and prevent collagen synthesis.ResultsHigh doses of arecoline (> 32 μg/ml) could inhibit human oral fibroblast proliferation, while low doses of arecoline (< 16 μg/ml) could promote the proliferation of human oral fibroblasts. Wnt5a was found to be both sufficient and necessary for the promotion of fibroblast proliferation. Egr-1 could mediate the expression of Wnt5a in fibroblasts, while NF-κB, FOXO1, Smad2, and Smad3 did not. Treatment with siRNAs specific to Egr-1, Egr inhibitors, or Wnt5a antibody treatment could all inhibit arecoline-induced Wnt5a upregulation and fibroblast proliferation.ConclusionsEgr-1 mediates the effect of low dose arecoline treatment on human oral mucosa fibroblast proliferation by transactivating the expression of Wnt5a. Therefore, Egr inhibitors and Wnt5a antibodies are potential therapies for treatment of oral submucosal fibrosis and oral cancer.
Highlights
Arecoline is an alkaloid natural product found in the areca nut that can induce oral submucous fibrosis and subsequent development of cancer
We found that low-dose arecoline treatment promoted human oral fibroblast proliferation and that Early growth response protein 1 (Egr-1) upregulated Wingless-type family member 5a (Wnt5a) expression to mediate the proliferative effect of arecoline treatment
Our results indicated that arecoline treatment promoted fibroblast proliferation at concentrations ranging from 0.1–16 μg/ml (Fig. 1b-f and Fig. S1), and the maximum effect on proliferation was observed at 8 μg/ml (Fig. 1e and Fig. S1)
Summary
Arecoline is an alkaloid natural product found in the areca nut that can induce oral submucous fibrosis and subsequent development of cancer. Chen et al BMC Molecular and Cell Biology (2020) 21:80 and migration, stimulate cell differentiation, and induce apoptosis [11,12,13,14], but some studies have observed that arecoline can promote the proliferation and migration of some cell types [15, 16]. Wnt family members are secreted glycoproteins that are highly conserved and play a key role in the regulation of fibroblast proliferation and tissue fibrosis [17,18,19,20]. Wnt family members may serve as ideal molecular targets for controlling fibroblast proliferation. The relationship between arecoline exposure and Wnt, as well as the transcription factors that control Wnt expression in oral fibroblasts, remain unclear
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