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    題名: 有機陽離子轉運蛋白 OCT2 增強胰臟癌細胞對 oxaliplatin 藥物敏感性之研究
    Organic cation transporter 2 sensitizes pancreatic cancer cells to oxaliplatin
    作者: 毛晨柔
    MAU, CHEN-ZOU
    貢獻者: 代謝與肥胖科學研究所碩士班
    邱慶豐
    關鍵詞: 胰臟癌;有機陽離子運輸蛋白2;多重抗藥性
    pancreatic cancer;organic cation transporter 2;multiple drug resistance
    日期: 2021-06-22
    上傳時間: 2022-01-02 22:28:47 (UTC+8)
    摘要: 目前胰臟癌的藥物治療包含gemcitabine、FOLFIRINOX和oxaliplatin等，然而治療效果常因抗藥性受限。有機陽離子運輸蛋白2 (organic cation transporter 2)，主要負責腎臟中含鉑藥物的運輸，如oxaliplatin。先前研究發現於多種癌症組織中，OCT2的表現量較正常組織少；而使用甲基化抑制劑decitabine可增加腎臟細胞癌中OCT2的表現量，進而提高癌細胞對oxaliplatin的敏感性。本研究藉由分析線上資料庫和從北醫聯合人體資料庫取得的檢體組織發現，OCT2基因在的於胰臟癌腫瘤組之表現顯著較正常控制組織組低。另外，胰臟癌抗gemcitabine藥物細胞株會影響OCT2蛋白的表現和功能，且OCT2蛋白表現與胰臟癌細胞株對oxaliplatin的敏感性呈現正相關。進一步研究探討OCT2表現背後的調控機制，發現具gemcitabine抗藥性的胰臟癌細胞株PANC-1/GR細胞中的OCT2啟動子幾個位點相較PANC-1細胞受到較高的甲基化情形。而decitabine可顯著增加PANC-1/GR細胞的OCT2表現和其對oxaliplatin的敏感性。另外，線上資料庫也呈現OCT2和DNA-甲基轉移酶 (DNMT1)呈現顯著的負相關，顯示OCT2的轉錄表現可能受到DNMT1甲基化的調控所抑制。除DNA甲基化的調控外，本研究還探討胰臟癌細胞株中OCT2受到蛋白酶體降解的情形，發現OCT2不論於胰臟癌細胞株或抗藥細胞株皆會受到蛋白酶體的降解作用。因此，結合decitabine或MG132與oxaliplatin都可能為胰臟癌治療帶來新治療策略。
    Gemcitabine, FOLFIRINOX and oxaliplatin have been chemo-therapy drugs for pancreatic cancer, however, the efficiency of these drugs are usually limited due to drug-resistance. Organic cation transporter 2 (OCT2), being a platinum drug transporter, mainly expresses on renal proximal tubule cells. Previous studies have shown that the expression of OCT2 is lower in several cancer tissues compared to its individual health control tissues. Based on Oncomine online database and the tissue samples collected from Joint BioBank of Taipei Medical University, OCT2 level of pancreatic tumor are significantly lower expression compared to its individual health control tissue samples. Moreover, we found that gemcitabine resistance of pancreatic cancer cells (PANC-1/GR and MIA Paca-2/GR) and parental PANC-1 and MIA Paca-2 cells were shown the positive correlation between OCT2 level and oxaliplatin. We further studied the underlying mechanism the regulation of OCT2 expression and found that OCT2 promoter region of PANC-1/GR cells have higher methylation frequency on several CpG sites compared to PANC-1 cells. Decitabine (DNA methyltransferase 1 inhibitor) treatment reversed the protein expression of OCT2 and enhanced the sensitivity of oxaliplatin in PANC-1/GR cells. Additionally, OCT2 and DNMT1 were shown significantly a negative correlation in pancreatic cancer tissues from Oncomine database, suggesting that transcription of OCT2 might be down-regulated by DNMT1 methylation. Besides regulation by DNA methylation, our study further investigated the protein degradation of OCT2 in pancreatic cancer cells. Proteasome inhibitors MG132 treatment was shown that OCT2 might go through proteasome degradation between PANC-1 and PANC-1/GR cells. In conclusion, combination of decitabine or MG132 with oxaliplatin treatments provide potential therapeutic strategies for pancreatic cancer.
    描述: 碩士
    指導教授：邱慶豐
    委員：張綺芬
    委員：吳泓璁
    資料類型: thesis
    顯示於類別:[代謝與肥胖科學研究所] 博碩士論文

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