次亞麻油酸在抑制肺癌轉移之角色探討及研究

Abstract

肺癌在全球癌症死亡人數比例中一直是名列前茅的佼佼者，除了因其不易被早期診斷外，另一項主要的原因就是患者有極高的機率在病程早期發生癌轉移的情況。目前，肺癌的治療仍存在許多的侷限性，轉移與藥物的抗藥性的產生是臨床常見的棘手問題，隨著病況的改變，病人往往需要接受更高強度的治療，伴隨而來的便是虛弱與副作用的發生；此時，許多的病人常會自行尋求營養補充像是亞麻籽油等以作為輔助治療，期望可以藉此延緩癌症進程。亞麻籽油富含大量α-次亞麻油酸(ALA)，其對於人類屬於一種必須脂肪酸，人體無法自行合成，須透過食物加以攝取，多數會儲存於身體組織中，進而在體內發揮潛在生理功能。目前，對於ALA是否能有效抑制肺癌細胞的轉移及其相關的調控機轉並不十分清楚；因此，在本研究中我們嘗試釐清ALA對於癌細胞侵襲與轉移能力之調控影響。首先，我們藉由細胞存活實驗找出不影響癌細胞增生之ALA添加劑量。後續，利用體外細胞培養的研究結果發現，ALA可促使高侵襲力肺癌細胞(CL1-2、CL1-5、Hop62和A549)產生類間質細胞上皮轉化 (MET-like)、抑制癌細胞的移動和侵襲、促進細胞骨架重排並使細胞整體的厚度增加。此外，我們利用全蛋白質體分析技術進一步找出可能參與ALA影響細胞轉移作用有關的作用蛋白並加以驗證。最後，更透過動物實驗以再次驗證ALA在動物體抑制肺癌轉移的能力。綜合上述結果，我們認為ALA在臨床上或許能作為一種有效的天然預防物，以協助延緩肺癌病患病情的惡化。

Lung cancer is the leading cause of cancer mortality worldwide. In addition to the delayed diagnosis, early metastasis and drug resistance are big challenges for lung cancer treatment, which not only accelerate cancer progression but also make patients more debilitated. Thus, many people tend to seek nutritional supports such as flaxseed oil to relieve their symptoms and hope to prolong their life. Flaxseed oil contains 50 to 60% alpha-linolenic acid (ALA), which is an essential fatty acid, stored in tissue pools, and benefits per se against cancer owing to its good bioavailability. Till now, the exact molecular mechanism of how ALA ameliorates cancer metastasis is still unclear. Thus, we tried to explore whether ALA treatment could affect the malignant behavior of highly invasive lung cancer cells. First, we determined the treatment concentration of ALA according to the IC50 of these cells. Then, we displayed that ALA treatments led cells to process mesenchymal-epithelial transition (MET), suppress their migratory and invasive abilities, promote cytoskeletal rearrangement, and increase cell thickness in vitro. Further, we identified potential candidates involved in ALA-mediated regulation of cancer metastasis through proteomic analysis. In the end, we demonstrated that ALA could inhibit lung cancer metastasis in vivo. All the results enlightened the role of ALA in inhibiting lung cancer metastasis.