α-次亞麻油酸對人類口腔鱗狀細胞癌細胞轉移與凋亡之分子機制

Molecular mechanisms of alpha-linolenic acid on metastasis and apoptotic cell death in human oral squamous cell carcinoma

施怡妏(Yi-Wen Shih)

指導教授 ： 李健群

中山醫學大學/健康管理學院/營養學系/碩士(2022年)

https://doi.org/10.6834/csmu202200106

摘要

口腔癌為全球最常見癌症之一，且為台灣十大癌症死因第六名。此類型口腔鱗狀細胞癌(oral squamous cell carcinoma, OSCC)具高度侵襲及轉移性，大多數預後不良患者有轉移之病程。因此，開發口腔癌之新穎療法為各國面臨之主要議題。次亞麻油酸(α-linolenic acid, ALA)為人體必需脂肪酸，先前研究證實其可藉由抑制上皮間質轉化(epithelial-mesenchymal transition, EMT)減少癌細胞轉移與侵襲。然而目前尚未闡明ALA對於口腔癌之抗癌活性。本研究旨在於探討ALA對SAS及GNM人類OSCC細胞之抗癌作用。結果顯示，ALA以劑量依賴性顯著減少癌細胞增生。以低濃度之ALA (100或200 μM)處理可抑制群落形成、Twist及EMT相關蛋白表現、MMP-2/-9蛋白表現與酵素活性，以及細胞移行與侵襲。以高濃度ALA (200或400 μM)處理顯著增加JNK磷酸化及c-jun之核累積，最終上調FasL/caspase8/caspase9/caspase3與Bid/cytochrome c/caspase9/caspase3路徑，進而導致口腔癌細胞凋亡。綜合上述結果，低濃度ALA可透過抑制Twist表現下調EMT相關蛋白或透過下調MMP-2/-9蛋白表現及酵素活性，抑制SAS及GNM OSCC細胞移行與侵襲。此外，高濃度ALA可藉由JNK/FasL/caspase 8/caspase 3-外源性凋亡路徑或Bid/cytochrome c/caspase 9/caspase 3-內源性凋亡路徑最終誘發SAS及GNM OSCC細胞凋亡。

關鍵字

次亞麻油酸 ； 上皮間質轉化 ； 轉移 ； 細胞凋亡 ； 口腔癌

並列摘要

Oral cancer is one of the most common cancer worldwide and ranks sixth among Taiwan’s top ten cancer causes. This type of oral squamous cell carcinoma (OSCC) has a highly invasive and metastatic capacity. Most of the patients with poor prognosis have a course of metastasis. Therefore, development of novel therapies for oral cancer is a major issue in various countries.. Alpha-linolenic acid (ALA), an essential fatty acid, has been shown to reduce cancer cell migration and invasion by inhibiting epithelial-mesenchymal transition (EMT). However, the anti-cancer activity of ALA on oral cancer has not been elucidated. The aim of this study is to investigate the anti-cancer effect of ALA on SAS and GNM human OSCC cells. The results showed that ALA significantly decreased cell proliferation in a concentration-dependent manner. Treatment with low concentrations of ALA (100 or 200 μM) reduce the colony formation, Twist and EMT-related protein expression, MMP-2/-9 protein expression and enzyme activity as well as cell migration and invasion. Treatment with high concentrations of ALA (200 or 400 μM) significantly increase the phosphorylation of JNK and the nuclear accumulation of c-jun, and subsequently upregulate the FasL/caspase8/ caspase3 and Bid/cytochrome c/caspase9/caspase3 pathway, which leads to OSCC cell apoptosis. Taken together, these results suggest that low concentration of ALA can inhibit SAS and GNM OSCC cell migration and invasion through suppression of Twist and down-regulating EMT-related proteins or by down-regulate the protein expression and enzyme activity of MMP-2/-9, while high concentration of ALA can promote apoptotic cell death though activation of JNK/FasL/caspase 8/caspase 3-extrinsic pathway and Bid/cytochrome c/caspase 9/caspase 3-intrinsic pathway in SAS and GNM OSCC cells.

並列關鍵字

α-linolenic acid ； epithelial-mesenchymal transition ； metastasis ； apoptosis ； oral cancer

參考文獻

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