探討鄰苯二甲酸酯誘發肝癌病程進展扮演之機制及其抑制劑

Studies on the mechanisms and inhibitor for phthalate-induced hepatocellular carcinoma progression

蔡承芳(Cheng-Fang Tsai)

指導教授 ： 郭柏麟

共同指導教授 ： 郭功楷(Kung-Kai Kuo)

高雄醫學大學/醫學院/醫學研究所博士班/博士(2016年)

摘要

依據衛福部死因統計，肝癌則為全國主要癌症死因的第二位。鄰苯二甲酸酯廣泛應用於工業之塑化劑，被認為是環境荷爾蒙，造成生殖及發育之毒性及和腫瘤發生相關。
在本論文第一部分我們發現鄰苯二甲酸丁基苯酯(BBP)會促進肝癌病程進展，其機轉透過AhR於細胞膜表面活化，並和G蛋白產生交互作用，引發下游訊息傳遞。AhR則是透過Non-genomic路徑，而非傳統genomic路徑作用。透過AhR/Gβ/PI3K/Akt/NF-κB pathway訊息傳遞路徑，BBP於體內具增加肝癌細胞移行(migration)及侵犯(invasion)之能力，於體外則具增加癌細胞轉移之能力。透過AhR/ERK/VEGF訊息傳遞路徑，BBP於體內、體外皆具增加血管新生之能力。
第二部分，我們發現鄰苯二甲酸二(2-乙基己基)酯(DEHP)除了促進肝癌細胞移行(migration)、侵犯(invasion)及上皮-間質轉換(epithelial-mesenchymal transition)之能力，亦增加癌幹細胞之比例，於體內則可促進腫瘤生長及轉移。我們首度發現薑黃素(curcumin)可抑制DEHP引起之肝癌細胞移行、侵犯、癌幹細胞之比例及體內之腫瘤生長及轉移，我們也證明上述作用透AhR/ERK/SK1/S1P3之訊息傳遞路徑。這些證據指出，薑黃素為具潛力之鄰苯二甲酸所引發之肝癌進展之抑制劑。
綜上所述，我們的研究顯示塑化劑可能促進肝癌進展及轉移的機制，可能和刺激癌幹細胞具正相關，並且我們發現薑黃素能拮抗這些作用，我們的研究，提供發展抑制劑的新契機。

關鍵字

鄰苯二甲酸酯 ； 肝癌

並列摘要

Hepatocellular carcinoma (HCC) is one of the most frequent cancers in the world. Phthalates, widely used as plasticizers and also known as hormone-mimicking chemicals, have been demonstrated to produce reproductive and developmental toxicity, and tumorigenesis.
In part I of this thesis, we found that benzyl butyl phthalate (BBP) affected HCC progression through the aryl hydrocarbon receptor (AhR), which then interacted with G proteins and triggered a downstream signaling cascade. BBP activated AhR via a nongenomic action involving G-protein signaling rather than through the classical genomic AhR action. BBP treatment promoted HCC migration and invasion in vitro and metastasis in vivo through the AhR/Gβ/PI3K/Akt/NF-κB pathway. In addition, BBP induced angiogenesis both in vitro and in vivo through the AhR/ERK/VEGF pathway.
In part II, our data showed that bis (2-ethylhexyl) phthalate (DEHP) promotes the migration, invasion, and epithelial-mesenchymal transition of HCC cells. In addition, DEHP increased the proportion of cancer stem cell (CSC)-like cells and enhanced stemness maintenance in vitro as well as tumor growth and metastasis in vivo. Importantly, we are the first to find that curcumin inhibited phthalate-induced cell migration, invasion and epithelial-mesenchymal transition, decreased the proportion of CSC-like cells in HCC cell lines in vitro, and suppressed tumor growth and metastasis in vivo through the inhibition of the AhR/ERK/SK1/S1P3 signaling pathway. Our results suggest that curcumin may be a potential inhibitor for phthalate-induced cancer progression.
In conclusion, the research clarifies the possible mechanism operated by phthalate in HCC progression and metastasis, and opens the avenue for antidote research.

並列關鍵字

phrhalate ； hepatocellular carcinoma

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