α-次亞麻油酸負向調控MDA-MB-231人類乳腺癌細胞ZEB-1基因表現及ZEB-1介導之細胞轉移作用

乳癌是女性最常見的癌症，也是造成女性死亡最主要的癌症。三陰性乳癌(Triple-negative breast cancer; TNBC)為不表現雌激素受體(estrogen receptor; ER)、黃體素受體(progesterone receptor; PR)和人類表皮生長因子受體(human epidermal growth factor receptor 2; HER-2)的乳癌亞型，其具有高侵襲性、轉移性、復發性及不良預後。ZEB-1為啟動上皮間質轉化(Epithelial-mesenchymal transition; EMT)的重要轉錄因子，使細胞從上皮型態轉為間質型態。ZEB-1啟動EMT已知可誘發三陰性乳癌的腫瘤轉移。α-次亞麻油酸(α-linolenic acid; ALA)為人體必需脂肪酸(essential fatty acid; EFA)，在乳腺癌中具有抗癌活性。雖然過去研究指出，ALA可以抑制EMT，然而ALA在乳腺癌細胞中抗轉移機制仍不清楚。ZEB-1是啟動EMT與促進MDA-MB-231乳腺癌細胞移行及侵襲的關鍵因子，本實驗將探討ALA對ZEB-1表現的影響。使用100 μM ALA及ZEB-1 siRNA處理後，測量ZEB-1蛋白表現及細胞移行與侵襲受抑制情形。ALA降低JNK磷酸化、p-IκB/ IκB比例與p65的核累積及ZEB-1 mRNA表達。此外，ALA透過抑制JNK和STAT3α的磷酸化，進而減少Slug的核累積，可能有助於抑制Slug介導EMT相關基因表達。總結，本研究結果顯示ALA不僅可以抑制EMT，同時抑制三陰性乳癌細胞ZEB-1調控的癌細胞轉移。

關鍵字

上皮間質轉化； α-次亞麻油酸； MDA-MB-231 ；轉移； ZEB-1

並列摘要

Breast cancer is the most common cancer in women and the first leading cause of cancer deaths in women. Triple-negative breast cancer (TNBC), a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2), has clinical features that including high invasiveness, high metastasis, proneness to relapse, and poor prognosis. ZEB-1 is a transcription factor that promotes epithelial-to-mesenchymal transition (EMT), allows the transition of epithelial cells into a mesenchymal state. ZEB-1 promotes EMT are known to induce tumor metastasis in TNBC. α-Linolenic acid (ALA), an essential fatty acid (EFA), has been reported to exhibit anticancer activity in breast cancer. Although ALA has been reported to suppress EMT, the underlying mechanism of the anti-metastasis effect of ALA in breast cancer cells remains unclear. We investigated the effect of ALA on ZEB-1, which is required to initiate EMT and promotes MDA-MB-231 breast cancer cell migration and invasion. Treatment with 100 μM ALA and ZEB-1 siRNA significantly decreased the ZEB-1 protein and cell migration and invasion. Moreover, ALA transiently attenuated the phosphorylation of JNK, p-IκB/IκB ratio and nuclear accumulation of p65 as well as and ZEB-1 mRNA expression. ALA decreased nuclear accumulation of Slug via decreasing phosphorylation of JNK and STAT3α, may contribute to inhibition of Slug-mediated EMT-relative genes expression. Taken together, our results indicate that ALA can be used not only to suppress EMT but also to abolish ZEB-1-mediated metastasis in TNBC cells.

並列關鍵字

EMT ； α-Linolenic acid ； MDA-MB-231 ； Metastasis ； ZEB-1

參考文獻

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α-次亞麻油酸負向調控MDA-MB-231人類乳腺癌細胞ZEB-1基因表現及ZEB-1介導之細胞轉移作用

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