Tsai Chung-Hung, Lee Shiuan-Shinn, Chang Yu-Chao
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Department of Oral Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.
J Oral Pathol Med. 2015 Oct;44(9):669-73. doi: 10.1111/jop.12284. Epub 2014 Nov 4.
Oral submucous fibrosis (OSF) is regarded as a pre-cancerous condition with fibrosis in oral subepithelial connective tissue. Hypoxia-inducible factor (HIF)-1α regulates a wide variety of profibrogenic genes, which are closely associated with tissue fibrosis. The aim of this study was to compare HIF-1α expression in normal buccal mucosa tissues and OSF specimens and further explore the potential mechanisms that may lead to the induction of HIF-1α expression.
Twenty-five OSF specimens and six normal buccal mucosa were examined by immunohistochemistry. The expression of HIF-1α from fibroblasts cultured from OSF and normal buccal mucosa was measured by Western blot. Arecoline, a major areca nut alkaloid, was challenged to normal buccal mucosa fibroblasts (BMFs) to elucidate whether HIF-1α expression could affect by arecoline. In addition, the effects of arecoline on plasminogen activator inhibitor (PAI)-1 expression were evaluated in environmental hypoxia.
HIF-1α expression was significantly higher in OSF specimens and expressed mainly by fibroblasts, epithelial cells, and inflammatory cells. Fibroblasts derived from OSF were found to exhibit higher HIF-1α protein expression than BMFs (P < 0.05). Arecoline was found to upregulate HIF-1α protein in a dose-dependent manner (P < 0.05). Hypoxia increased arecoline-induced PAI-1 protein expression than normoxic conditions (P < 0.05).
These results suggest that HIF-1α expression is significantly upregulated in OSF tissues from areca quid chewers, implying a potential role as a biomarker for local tissue hypoxia. The activation of HIF-1α may promote fibrogenesis by an increase of PAI-1 expression and a subsequent elevation of extracellular matrix production in oral submucosa leading to fibrosis.
口腔黏膜下纤维化（OSF）被视为一种口腔上皮下结缔组织纤维化的癌前病变。缺氧诱导因子（HIF）-1α调节多种促纤维化基因，这些基因与组织纤维化密切相关。本研究旨在比较正常颊黏膜组织和OSF标本中HIF-1α的表达，并进一步探讨可能导致HIF-1α表达诱导的潜在机制。
采用免疫组织化学法检测25例OSF标本和6例正常颊黏膜。通过蛋白质免疫印迹法检测从OSF和正常颊黏膜培养的成纤维细胞中HIF-1α的表达。槟榔碱是槟榔的主要生物碱，用其刺激正常颊黏膜成纤维细胞（BMF），以阐明HIF-1α表达是否受槟榔碱影响。此外，在环境缺氧条件下评估槟榔碱对纤溶酶原激活物抑制剂（PAI）-1表达的影响。
OSF标本中HIF-1α表达显著升高，主要由成纤维细胞、上皮细胞和炎性细胞表达。发现源自OSF的成纤维细胞比BMF表现出更高的HIF-1α蛋白表达（P < 0.05）。发现槟榔碱以剂量依赖方式上调HIF-1α蛋白（P < 0.05）。与常氧条件相比，缺氧增加了槟榔碱诱导的PAI-1蛋白表达（P < 0.05）。
这些结果表明，咀嚼槟榔者的OSF组织中HIF-1α表达显著上调，这意味着其作为局部组织缺氧生物标志物的潜在作用。HIF-1α的激活可能通过增加PAI-1表达以及随后口腔黏膜下层细胞外基质产生增加导致纤维化，从而促进纤维生成。
