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標題: 蘆薈大黃素透過降低Y-box致癌因子進而抑制HER-2表現在第二型人類表皮生長因子接受體過度表現的乳癌之研究
Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells
作者: 馬瑞彣
Jui-Wen Ma
關鍵字: 人類第二型類上皮生長因子接受體;蘆薈大黃素;上皮細胞間質轉化;Y-box結合蛋白1;human epidermal growth factor type II;aloe-emodin;Epithelial-Mesenchymal Transition;Y-Box Binding Protein 1
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乳癌為國人女性死因第四名,目前乳癌治療依據患者雌激素接受體(Estrogen Receptor, ER)、黄體素接受體(Progesterone Receptor, PR)及人類第二型類上皮生長因子接受體(Human Epidermal Growth Factor Receptor Type-2, HER-2)等腫瘤標記進行個人化醫療。乳腺癌細胞大量表現人類表皮生長因子受體2(HER-2)往往更具攻擊性、高轉移性及耐藥性。過去文獻指出,大黃素(emodin)是大黃植物(Rheum palmatum L.)根中的主要化合物,具有顯著抑制HER-2之表現量。本研究主旨乃在於比較大黃素類似物,大黃素(emodin)、蘆薈大黃素(aloe-emodin; AE)及大黃酸(rhein)對於抑制HER-2表現量的效果。研究證實,AE處理HER-2過度表現之乳腺癌細胞株,具有最顯著抑制HER-2蛋白表現量。有趣的是,AE抑制HER-2蛋白的表現量,主要是透過降低致癌蛋白YB-1所造成,並且在AE處理後,降低了細胞遷移和侵襲的能力。結果也表明,AE抑制癌細胞轉移蛋白Twist及vimentin的表現量,並證實AE主要透過抑制ILK / AKT / mTOR信息路徑,進而降低YB-1的表現量。體內研究證實,裸鼠誘導人類HER-2過度表達之乳腺癌腫瘤,經由AE處理後可顯著性的抑制腫瘤生長。這些研究結果可提供AE作為未來策略性治療HER-2過度表現之乳腺癌患者的用藥選擇之一。

Breast cancer is the fourth leading cause of death of female in Taiwan, The current treatment of patients with breast cancer target estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor type II (HER-2) receptor type and other tumor markers for personalized medicine. Human epidermal growth factor receptor-2 (HER-2)-positive breast cancer tends to be aggressive, highly metastatic, and drug resistant and spreads rapidly. Studies have indicated that emodin inhibits HER-2 expression. This study compared the HER- 2-inhibitory effects of two compounds extracted from rhubarb roots: aloe-emodin (AE) and rhein. Our results indicated that AE exerted the most potent inhibitory effect on HER-2 expression. Treatment of HER-2-overexpressing breast cancer cells with AE reduced tumor initiation, cell migration, and cell invasion. AE was able to suppress YB-1 expression, further suppressing downstream HER-2 expression. AE suppressed YB-1 expression through the inhibition of Twist in HER-2-overexpressing breast cancer cells. Our data also found that AE inhibited cancer metastasis and cancer stem cells through the inhibition of EMT. Interestingly, AE suppressed YB-1 expression through the downregulation of the intracellular integrin-linked kinase (ILK)/protein kinase B (Akt)/mTOR signaling pathway in HER-2-overexpressing breast cancer cells. In vivo study showed the positive result of antitumor activity of AE in nude mice injected with human HER-2-overexpressing breast cancer cells. These bindings suggest the possible application of AE in the treatment of HER-2-positive breast cancer.
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