白藜蘆醇甲基衍生物3,5,4

蔡杰亨

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白藜芦醇甲基衍生物3,5,4'-Trimethoxystilbene及槲皮素调节乳癌细胞侵犯及反转上皮-间质转化效果之机制探讨

Effects of resveratrol methoxylated analog 3,5,4'-Trimethoxystilbene and Quercetin on the regulation of breast cancer invasion and the reversion of epithelial-to-mesenchymal transition

蔡杰亨 , 博士　　导师：陈威仁;许立松　　

英文

乳癌；上皮细胞-间质细胞转换；槲皮素； breast cancer ； epithelialmesenchymal transition ； quercertin

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摘要 │ 参考文献 (133) │ 国际计量

摘要〈TOP〉

乳癌是世界上妇女常见死亡原因之一。近期研究发现乳癌细胞侵袭力的获得和晚期的转移与乳癌细胞型态上的上皮细胞-间质细胞转换(epithelial- mesenchymal transition，EMT) 有极为密切的关聯，因为EMT可以赋予乳癌细胞呈现肿瘤起始细胞与癌症干细胞的特性，进而促进乳癌细胞的扩散与转移。Wnt/β-catenin和Type I insulin-like growth factor receptor (IGF-1R)讯号路径号的失调是EMT转换的主要机制之一。因此，若能藉由白藜芦醇甲基衍生物3,5,4’- trimethoxystilbene (MR-3) 及黄酮类化合物槲皮素 (quercertin) 抑制Wnt/β-catenin或IGF1R讯号路径活化所造成的癌细胞EMT，或许能够降低乳癌的转移与致死率。对於研究乳癌转移机制及现行的预後与治疗策略也有重要的帮助，而且目前关於研究MR-3及槲皮素抑制乳癌转移过程相关分子机制的也尚未明了 。   因此，本论文第一部份的研究，MR-3抑制乳癌细胞的上皮细胞-间质细胞转换，以MR-3处理MCF-7人類乳癌细胞株，发现MR-3确实能够增加MCF-7细胞中epithelial-like marker E-cadherin的表现，回復cobblestone-like细胞形态，并同时抑制mesenchymal-like markers如snail，slug与vimentin等之表现。此外，MR-3逆转EMT的同时，亦抑制了MCF-7细胞在transwell assay下侵袭与转移的能力。进一步探讨MR-3逆转MCF-7细胞EMT之作用机转，发现MR-3会减少β-catenin在细胞核的堆积，降低β-catenin下游基因的表现，并同时增加membrane-bound β-catenin的出现。另一方面，MR-3亦透过抑制Phosphatidylinositol 3-kinase (PI3K) /Akt的活化，來增加Glycogen synthase kinase 3 beta (GSK-3β) 稳定性与活性，而GSK-3β会促成β-catenin经由ubiquitin proteasome pathway 被分解。因此，我们推论MR-3可能是先藉由调节PI3K/Akt/GSK-3β讯号路径的活性，进而抑制β- catenin进入细胞核与减少其下游基因的表现，來促使MCF-7细胞EMT的逆转与降低其侵袭力。   第二部分研究quercetin藉由调节IGF1R讯号路径的活性，來减少三阴性乳癌细胞株MDA-MB-231的EMT转换，藉由抑制insulin-like growth factor-1 (IGF-1)分泌及ADAM Metallopeptidase Domain 28 (ADAM28)表现，增加Insulin-like growth factor-binding protein 3 (IGFBP-3)在细胞培养液中浓度，抑制三阴性乳癌细胞的侵袭力亦影响了MDA-MB-231细胞Matrix Metalloproteinases- 2 (MMP-2), Matrix Metalloproteinases- 9 (MMP-9), urokinase plasminogen activator (uPA)与乳癌干细胞分子标记Oct4、Sox2与Nanog等的表现。同时，quercetin亦抑制vimentin、fibronetin与vascular endothelial growth factor (VEGF) 等间质相关标记的表现，并促进keratin-18, keratin -19与ZO-1等上皮相关标记表现。Quercetin透过降低的IGF1R磷酸化程度，影响IGF1R激酶之受质Insulin receptor substrate 1 (IRS1) 的磷酸化和IGF1R下游Akt与 MAPK/ERK 之活性产生抑制作用。而如同quercetin对於IGF1R讯号传递路径的活性的影响，quercetin亦明显降低EMT转换之相关转錄因子，包含snail、slug与zeb1在蛋白质与mRNA的表现同时减少snail与slug启动子的活性。最後以小鼠人類乳癌移植瘤动物实验模式，证明quercetin确实能有效抑制ADAM28和IGF1R讯号传递路径对MDA-MB-231乳癌移殖瘤的肺转移与EMT转换之影响。   总而言之，综合以上研究，本论文指出白藜芦醇甲基衍生物MR-3和槲皮素皆具有抑制上皮-间质转化及侵袭性功效。分别透过不同分子机制来调控细胞上皮-间质转化，MR-3主要透过抑制Wnt/β-catenin的讯号传递路径而槲皮素是透过增加IGFBP-3分泌抑制IGF-1R传递路径。

并列摘要〈TOP〉

Breast cancer is the most common cancer in women worldwide. Epithelial- mesenchymal transition (EMT) was demonstrated to be one of the major mechanisms responsible for mediating invasiveness and metastasis of late-stage cancers. The molecular basis of EMT functions as a potential therapeutic target for breast cancer because EMT may endow breast tumor-initiating cells with stem-like characteristics and enable the dissemination of breast cancer cells. Understanding the mechanisms of 3,5,4’-trimethoxystilbene and quercetin in breast cancer metastasis will greatly improve diagnostic or interceptive strategies. 
In the part I, We have examined a series of resveratrol methoxylated derivative of to explore their cellular on EMT and the invasiveness of human MCF-7 breast adenocarcinoma cell line were also explored for further development of new chemotherapeutic agents. We found that MR-3 significantly increased epithelial marker E-cadherin expression and decreasing of mesenchymal markers, such as snail, slug, and vimentin. In parallel with EMT reversal, MR-3 downregulated the invasion and migration of MCF-7 cells. Exploring the action mechanism of MR-3 on the suppression of EMT and invasion indicates that MR-3 markedly reduced the expression and nuclear translocation of β-catenin, accompanied with the downregulation of β-catenin target genes and the increment of membrane-bound β-catenin. MR-3 restored glycogen synthase kinase-3β activity by inhibiting the phosphorylation of Akt, the event required for β-catenin destruction via a proteasome-mediated system. These findings indicate that the anti-invasive activity of MR-3 on MCF-7 cells may result from the suppression of EMT via down-regulating phosphoinositide 3-kinase (PI3K)-AKT signaling, and consequently, β-catenin nuclear translocation.
  In the part II, we investigated quercetin can suppress the Type I insulin-like growth factor (IGF-1) growth axis may be of preventive or therapeutic value. We have demonstrated quercetin modulates Type I insulin-like growth factor receptor (IGF1R) signaling through upregulation of Insulin-like growth factor-binding protein 3 (IGFBP-3) and downregulation IGF-1 secretion and ADAM Metallopeptidase Domain 28 (ADAM28) expression . In this study, we investigated the mechanism of quercetin can induce the reversion of EMT . Quercetin down-regulation mesenchymal- like markers vimentin、fibronetin and vascular endothelial growth factor (VEGF) and up-regulated epithelial-like markers keratin-18, -19 and ZO-1 proteins expression。Quercetin also inhibition of IGF-1R and IRS-1 phosphorylation and decrease IGF-1R downstream signaling molecules AKT and ERK1/2 phosphorylation. The transcript levels of transcription factors involved in EMT control, such as snail, slug, and zeb1 were reduced in protein and mRNA levels and downregulation of snail and slug activation in MDA-MB-231 cells after quercetin treatment. In vivo administration of quercetin to MDA- MB-231 tumor xenografts inhibited tumor growth and lung metastasis, resulted in IGF-IR inactivation and regulation ADAM28. These results suggest that inhibition of cell invasive activity and metastasis induction of IGFBP-3 and by Quercetin are mediated inhibition of IGF-IR signaling pathway.
  Taken together, these findings indicate that resveratrol methoxylated analog MR-3 and quercetin lead to the blockage of EMT and the invasion of breast cells. We found that MR-3 inhibitor of Wnt/β-catenin signaling and quercetin increas level of IGFBP- 3 through aberrant regulation of IGF-1R signaling.

参考文献 ( 133 ) 〈TOP〉

1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A: Global cancer statistics, 2012. CA Cancer J Clin 2015, 65(2):87-108.
连结：
2. Ou-Yang F, Hsu NC, Juan CH, Huang HI, Moi SH, Chen FM, Liu TW, Hou MF: Breast cancer quality of care in Taiwan in relation to hospital volume: a population-based cohort study. Asia Pac J Clin Oncol 2015, 11(4):308-313.
连结：
3. Ho ML, Hsiao YH, Su SY, Chou MC, Liaw YP: Mortality of breast cancer in Taiwan, 1971-2010: temporal changes and an age-period-cohort analysis. J Obstet Gynaecol 2015, 35(1):60-63.
连结：
4. Tseng CH: Prolonged use of human insulin increases breast cancer risk in Taiwanese women with type 2 diabetes. BMC Cancer 2015, 15:846.
连结：
5. Cristofanilli M, Gonzalez-Angulo A, Sneige N, Kau SW, Broglio K, Theriault RL, Valero V, Buzdar AU, Kuerer H, Buchholz TA et al: Invasive lobular carcinoma classic type: response to primary chemotherapy and survival outcomes. J Clin Oncol 2005, 23(1):41-48.
连结：

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引用含有DOI的文献

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。 如想对DOI的使用与概念有进一步了解，请参考 （ ） 。

DOI可强化引用精确性、增强学术圈连结，并给予使用者跨平台的良好使用经验，目前在全世界已有超过五千万个对象申请DOI。如想对DOI的使用与概念有进一步了解，请参考（）。