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研究生： 施秉宏
Shih, Ping-Hung
論文名稱： 卵巢癌細胞株內脂質與膽固醇含量之研究
The study of lipid and cholesterol contents in ovarian cancer cells
指導教授： 蔡世峯
Tsai, Shih-Feng
楊嘉鈴
Yang, Jia-Ling
口試委員: 江士昇
Jiang, Shih-Sheng
喻秋華
Yuh, Chiou-Hwa
潘文涵
Pan, Wen-Harn
學位類別： 碩士
Master
系所名稱： 生命科學暨醫學院 - 分子醫學研究所
Institute of Molecular Medicine
論文出版年： 2019
畢業學年度： 107
語文別： 英文
論文頁數： 107
中文關鍵詞： 卵巢癌 、脂質 、膽固醇 、膽固醇含量 、脂質含量
外文關鍵詞： lipid, cholesterol, lipid contents, cholesterol contents, ovarian cancer
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    • 近25年來台灣卵巢癌的發生率上升了一倍，雖然卵巢癌在台灣的發生率並不是癌症中最高的，但卵巢癌卻是最致命的婦科癌症，卵巢癌之所以能造成婦科癌症中最高的死亡率，是因為卵巢癌很難發現並且容易復發，不幸的是即使是在接受治療後三年內的復發率還是高達75％，而一旦卵巢癌復發，通常伴隨著化學藥物抗性的產生。

    在正常細胞中，氧化膽固醇和膽固醇的含量會保持平衡，在快速增殖細胞如癌細胞中，細胞將偏向讓膽固醇保持在高水平而讓氧化膽固醇的含量下降，以提供形成細胞膜的所需的材料和細胞生長所需的能量，氧化膽固醇的下降會導致肝X受體（LXR）的活性下降，因為LXR是一種核受體，在結合上氧化膽固醇後被活化並且促進下游基因的表達，包括ATP-binding cassette transporter (ABC transporter) ABCG1和ABCG4，ABCG1和ABCG4能將脂質和膽固醇轉運細胞膜外，最近的研究發現，膽固醇的累積與卵巢癌的化療藥物抗性有關，如果可以激活LXR，增加ABCG1和ABCG4表現量，那就能使脂質和膽固醇從細胞內向外排出並減少癌細胞的增殖。

    為了激活LXR，我們使用了LXR活化劑TO901317代替氧化膽固醇，TO901317可以促使LXR與LXR反應元件（LXRE）的結合，並增加下游基因ABCG1和ABCG4的表達。根據即時聚合酶連鎖反應和西方墨點法的結果，TO901317添加後，增加ABCG1和ABCG4的信使核糖核酸和蛋白質的表達在四種卵巢癌細胞株A1847、A2780、SKOV3、TOV-112D中，且與添加TO901317的濃度呈正相關。ABCG1和ABCG4都是ABC transporter，它們能消耗ATP將細胞內的脂質和膽固醇運送到細胞膜外，我們使用Oil Red O staining來檢測在細胞培養基中加入TO901317之前和之後脂質和膽固醇的濃度變化，來測試ABCG1和ABCG4的功能。結果發現只需要在卵巢癌細胞株中加入5μM的TO901317，細胞膜內脂質和膽固醇的濃度就會開始降低。最後我們測試了卵巢癌細胞株在加了TO901317並被影響了脂質和膽固醇含量後癌細胞的增殖速度變化，結果顯示當TO901317的濃度增加至超過5μM時，細胞增殖速度將會減少，綜合以上所述，本論文研究顯示：（一）TO901317能透過活化LXR去增加ABCG1和ABCG4的表達量，（二）TO901317能透過ABCG1和ABCG4去降低卵巢癌細胞株內的脂質和膽固醇的濃度，（三）TO901317可以降低卵巢癌細胞株的增殖速度。綜合以上因此我們推論LXR活化劑TO901317有潛力成為治療卵巢癌的新方法。

    In the recent 25 years, the incidence rate of ovarian cancer has doubled in Taiwan. Although the incidence rate of ovarian cancer is not the highest, ovarian cancer is the most lethal gynecologic cancer. Ovarian cancer causes the highest mortality rate because it is hard to diagnosed and easy to relapse. Ovarian cancer patients usually are asymptomatic until the late stage. After initial treatment, ovarian cancer still has a high recurrence rate. Unfortunately, the relapse rate in three years after receiving the therapy can be as high as to 75%. Once the relapse occurs, it usually combines with the chemoresistance.
    In the normal cell, the level of oxysterol and cholesterol are kept balanced. In the highly proliferating cancer cells, high level of cholesterol is required to provide energy and building block for the cell membranes. Low oxysterol leads to the low activity of liver X receptor (LXR), which is a nuclear receptor that regulates the downstream genes such as ATP-binding cassette transporter ABCG1 and ABCG4, which can transport lipid and cholesterol out of the cell membrane. Recent research revealed that cholesterol is related to the chemoresistance in ovarian cancer. Activation of LXR increases the expression of ABCG1 and ABCG4 leads to lipid and cholesterol efflux from the cell and decreases the proliferation of cancer cells.
    In this study, we used the LXR agonist TO901317 instead of the natural ligand oxysterol to activate the LXR. TO901317 could enhance LXR binding to LXR response element (LXRE) and increased the expression of downstream genes ABCG1 and ABCG4. According to the qPCR and western blot results, the mRNA and protein level of ABCG1 and ABCG4 were increased upon adding TO901317 to the ovarian cancer cell lines A1847, A2780, SKOV3, and TOV-112D in a dosage dependent manner. ABCG1 and ABCG4 are both the ABC transporter that consume ATP to transport the lipid and cholesterol out of the cell membranes. To examine the function of ABCG1 and ABCG4, Oil Red O staining was used to detect the change of lipid and cholesterol level after adding TO901317 to the cell medium. The result indicated that 5μM of TO901317 was sufficient to decrease the lipid and cholesterol levels. Finally, the cell proliferation was determined after addition of TO901317 to the cells. We found the concentration over 5μM decreased the cell proliferation. Taking together, we conclude that TO901317 can reduce ovarian cancer cell proliferation by decreasing the lipid and cholesterol level through the activation of ABCG1 and ABCG4. Thus, LXR agonist TO901317 could be a potential therapeutic means for treating ovarian cancer.

    Abstract 2 中文摘要 3 誌謝辭 4 Content 5 Chapter 1. Introduction 8 1.1 Ovarian cancer 8 1.1.1 Overview 8 1.1.2 Surgery 8 1.1.3 The response of taxanes 9 1.1.4 The response of platinum 9 1.1.5 The incidence rate and mortality rate of Ovarian cancer 9 1.1.6 The chemoresistance of ovarian cancer 11 1.2 Liver X receptor 13 1.3 Homeostasis of cholesterol and oxysterol 17 1.4 ABCA and ABCG 21 Reason and hypothesis 25 Chapter 2 Materials and methods 27 2.1 Cell culture 27 2.2 TO901317 29 2.3 RNA Extraction from Cultured Cells 30 2.4 Reverse transcription 32 2.5 Qubit assays for DNA and RNA 33 2.6 Real-time polymerase chain reaction (qPCR) 34 2.7 Protein extraction 36 2.8 Western blot 39 2.9 Oil red o staining with normal medium 43 2.10 Oil red o staining with the medium has a fatty acid 46 2.11 MTS 50 Chapter 3 Results 51 3.1 The mRNA level changed of ABCG1 and ABCG4 after adding TO901317 to the cells 51 3.2 The Protein level changed of ABCG1 and ABCG4 after adding TO901317 to the cells 53 3.3 Lipid and cholesterol level changed in different medium and concentration of TO901317 55 3.4 Cell proliferation affected by TO901317 59 Chapter 4 Discussion 61 Chapter 5 Conclusion 67 Figures 68 Fig. 1. The qPCR result of the cancer cell line A1847. 69 Fig. 2. The qPCR result of the cancer cell line A2780. 71 Fig. 3. The qPCR result of the cancer cell line SKOV3. 73 Fig. 4. The qPCR result of the cancer cell line TOV-112D. 75 Fig. 5. The protein level of ABCG1 and ABCG4 in the ovarian cancer cell line A1847 after adding TO901317. 76 Fig. 6. The protein level of ABCG1 and ABCG4 in the ovarian cancer cell line A2780 after adding TO901317. 77 Fig. 7. The protein level of ABCG1 and ABCG4 in the ovarian cancer cell line SKOV3 after adding TO901317. 78 Fig. 8. The protein level of ABCG1 and ABCG4 in the ovarian cancer cell line TOV-112D after adding TO901317. 79 Fig. 9. The protein level of ABCG1 and ABCG4 in the immortalized ovarian surface epithelial cell IOSE after adding TO901317. 80 Fig. 10. The lipid and cholesterol level of the ovarian cancer cell line A2780 in different concentration of TO901317 81 Fig. 11. The lipid and cholesterol level of the ovarian cancer cell line SKOV3 in different concentration of TO901317 82 Fig. 12. The lipid and cholesterol level of the ovarian cancer cell line TOV-112D in different concentration of TO901317 83 Fig. 13. The lipid and cholesterol level of the immortalized ovarian surface epithelial cell IOSE in different concentration of TO901317 84 Fig. 14. The cell viability of ovarian cancer cell line A1847 in different concentrations of TO901317. 85 Fig. 15. The cell viability of ovarian cancer cell line A2780 in different concentrations of TO901317. 87 Fig. 16. The cell viability of ovarian cancer cell line SKOV3 in different concentrations of TO901317. 89 Fig. 17. The cell viability of ovarian cancer cell line TOV-112D in different concentrations of TO901317. 90 Fig.18. The cell viability of the immortalized ovarian surface epithelial cell IOSE in different concentrations of TO901317. 91 Chapter 6 Supplements 92 Fig. 6-1. Incidence rates of all gynecologic cancers in Taiwan16 92 Fig. 6-2. Age-specific rate of ovarian cancer in Taiwan16 93 Fig. 6-3. Ascites cholesterol affects the chemotherapy56 93 Fig. 6-4. Cellular cholesterol affects the chemotherapy56 94 Fig. 6-5. Adipose tissue affects tumour cells74 94 Fig. 6-6. Adipose tissue affects tumour cells74 95 Fig. 6-7. TO901317 in LXR ligand-binding pocket of LXRα75 95 Fig. 6-8. Ovarian cancer incidence and death rate in USA17. 96 Fig. 6-9. ABCG1 and ABCG4 mRNA expression of ovarian cancer cell lines in qPCR data 97 Fig. 6-10. Using ImageJ to calculate the density of western blot band 98 Fig. 6-11. Lipid and cholesterol level of the ovarian cell after adding TO901317 99 Fig. 6-12. Lipid and cholesterol level of the ovarian cell after adding TO901317 and palmitate 99 Fig. 6-13. Lipid and cholesterol level of the ovarian cell after adding TO901317 and oleate 100 Fig. 6-14. Cell viability of ovarian cancer cell after adding TO901317 101 Chapter 7 References 102

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