Arecoline 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. High 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. Egr-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.

中文翻译：

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Egr-1通过反式激活Wnt5a表达介导小剂量槟榔碱诱导的人口腔黏膜成纤维细胞增殖

槟榔碱是在槟榔中发现的一种生物碱天然产物，可以诱导口腔粘膜下纤维化和随后的癌症发展。但是，大量研究表明槟榔碱可能抑制成纤维细胞增殖并阻止胶原蛋白合成。高剂量槟榔碱（> 32μg/ ml）可以抑制人口腔成纤维细胞的增殖，而低剂量槟榔碱（<16μg/ ml）可以促进人口腔成纤维细胞的增殖。发现Wnt5a对于促进成纤维细胞增殖既足够又必要。Egr-1可以介导Wnt5a在成纤维细胞中的表达，而NF-κB，FOXO1，Smad2和Smad3则不能。用特异性针对Egr-1，Egr抑制剂或Wnt5a抗体的siRNA进行治疗均可抑制槟榔碱诱导的Wnt5a上调和成纤维细胞增殖。Egr-1通过反式激活Wnt5a的表达来介导低剂量槟榔碱治疗对人口腔粘膜成纤维细胞增殖的影响。因此，Egr抑制剂和Wnt5a抗体是用于治疗口腔粘膜下纤维化和口腔癌的潜在疗法。