香草醛對口腔鱗狀細胞癌上皮間質轉化作用及轉移力之抑制效應

口腔鱗狀細胞癌是口腔最常見之惡性上皮腫瘤。口腔癌位居2023年國人十大癌症死亡率第六，且晚期口腔癌五年內復發率及死亡率高。增加上皮間質轉化(Epithelial Mesenchymal transition, EMT)與基質金屬蛋白酶(Matrix metalloproteinase, MMP)，表現及活性，為啟動癌細胞移行與侵襲之重要因子，亦是造成預後不佳及高死亡率主因。香草醛(Vanillin)為由香草莢萃取出的主要活性成分，常用於食品加工。研究證實香草醛具有抗氧化、抗發炎及抗癌作用。然而，香草醛如何影響口腔癌發展尚不清楚，其調控機制仍有待釐清。本研究以SAS人類口腔鱗狀細胞癌模式，探討香草醛是否調控EMT與MMPs而影響癌細胞轉移。結果顯示2 mM香草醛顯著減少MMP-2、MMP-9蛋白表現與酵素活性，且香草醛減少STAT3、Snail1、Slug和Twist1由細胞質轉位至細胞核。此外，香草醛下調STAT3、Snail1、Slug和Twist1 mRNA及其下游標的蛋白如α-SMA、Fibronectin和Vimentin表現下降，而E-cadherin表現上升。利用si-RNA將STAT3、Snail1、Slug、Twist1 knockdown後顯著抑制α-SMA、Fibronectin、Vimentin等EMT相關蛋白表現，此結果與香草醛抑制效果類似。傷口癒合及侵襲試驗結果發現香草醛抑制癌細胞移行與侵襲。綜合上述結果，香草醛可能透過下調MMP-2、MMP-9表現和STAT3、Snail1、Slug、Twist1所啟動之EMT進而抑制SAS人類口腔鱗狀細胞癌轉移。

Oral squamous cell carcinoma is the most common maligant epithelial neoplasm in oral cavity. In 2023, oral cancer ranks the sixth in cancer mortality in Taiwan, and recurrence rate and mortality rate of advanced oral cancer within five years are high. Induction of epithelial-mesenchymal transition (EMT) and matrix metalloproteinases (MMPs) are important factors in initiating cancer cell migration and invasion, contributing to poor prognosis and high mortality. Vanillin, a major active compound extracted from vanilla pods, is commonly used in food processing and possesses. It has been shown that Vanillin has potent antibacterial, antioxidant, and anticancer properties. However, it remains unclear how vanillin affects oral cancer development, and the regulatory mechanisms are not fully understood. In this study, SAS, a human oral squamous cell carcinoma cell line was used to investigate whether vanillin affects cancer cell metastasis by modulating EMT and MMPs. These results showed that 2 mM vanillin significantly reduced the protein expression and enzymatic activity of MMP-2 and MMP-9, and it suppressed the translocation of STAT3, Twist1, Snail1and Slug from cytosol to nucleus. Moreover Vanillin downregulated the mRNA levels of STAT3, Twist1, Snail1and Slug as well as the expression of downstream target proteins such as α-SMA, fibronectin, and vimentin, while E-cadherin expression was increased. Silencing STAT3, Snail1, Slug, and Twist1 by si-RNA significantly suppressed the expression of EMT-related proteins including α-SMA, fibronectin, and vimentin, which mimics the results for vanillin treatment. Wound healing and invasion assays demonstrated that vanillin inhibited cancer cell migration and invasion. Conclusion, these results suggested that vanillin suppresses metastasis by down-regulateing MMP-2 and MMP-9 expression and STAT3, Snail1, Slug, and Twist1, mediating EMT in SAS oral squamous cell carcinoma.