K他命和嗎啡常用於緩解手術、慢性病及癌症病患的疼痛。K他命會拮抗NMDA（N-methyl-d-aspartate）受體以降低神經元的輸出。嗎啡會與μ–δ-opioid受體異二聚體相互作用。K命和嗎啡都有成癮性，有時會用作娛樂性藥物。雖然嗎啡用於減輕晚期癌症患者的疼痛，但有研究指出嗎啡會抑制免疫細胞並促進腫瘤進展。目前尚不清楚K他命是否會有類似的作用。在本研究中，我們探討了K他命和嗎啡成癮小鼠乳癌生長的情況及可能的機制。為了闡明這些機制，動物實驗發現與注射生理鹽水的小鼠相比，注射K他命和嗎啡成癮的小鼠，乳癌腫瘤體積和重量增加且發現更高的肺轉移發生率。為了解K他命和嗎啡如何影響腫瘤生長和轉移，進行RNA定序（RNA Sequencing），試著分析 K他命成癮組腫瘤和生理食鹽水組基因表達圖譜的差異性。我們使用KEGG（Kyoto Encyclopedia of Genes and Genomes）及GO-term（Gene Ontology）分析RNA定序的數據。根據分析，K他命成癮組腫瘤中表現量上升的基因參與了許多導致癌症的生物信號路徑，並且正向調控了細胞遷移、增殖，其中包括BMP5、EGFR、WNT5A基因。然而在細胞實驗中，使用不同濃度的K他命或嗎啡接觸細胞，並且沒有發現癌細胞增殖，但細胞的侵襲和遷移能力增加。我們的研究結果顯示，K他命和嗎啡的成癮增加乳癌腫瘤中BMP5、EGFR、WNT5A的表現量並促進乳癌細胞轉移。臨床上使用這些藥物的患者，可能需要改變用藥的策略或使用代替的藥物，而吸毒者必須引以為戒。

Ketamine and morphine are common pain eliever often used as palliative medicine. Ketamine antagonizes the N-methyl-d-aspartate (NMDA) receptor to decrease neuronal output. Morphine is an opioid that interacts predominantly with the μ–δ-opioid receptor heterodimer. Ketamine and morphine are both addictive and sometimes used as recreational drugs. While morphine is used for late stage cancer patients to reduce pain, morphine has been shown to inhibit immune cells and promote tumor progression. It is not known whether ketamine would exert similar effect. In this study, we investigated the possible mechanisms and effects of breast tumor growth in ketamine and morphine-addicted mice. In in vivo studies, we found that mice with ketamine addiction had increased volume and weight of tumors compared to mice treated with saline. In addition, higher incidence of lung metastasis was observed for mice addicted with ketamine and morphine. To understand how ketamine and morphine affect tumor growth and metastasis, RNA-sequencing (RNA-seq) analysis was performed to compared gene expression profiles among animals with or without addiction of ketamine or morphine. KEGG and GO analysis were used to analyze the data of RNA-seq. According to the analysis, a number of cancer signaling-related genes were up-regulated, including BMP5, EGFR, and WNT5A. While proliferation and colony formation of EO771 cells treated with different concentrations of ketamine and morphine was not affected, cell invasion and migration were increased. In conclusion, addiction of ketamine and morphine upregulate the expression of BMP5, EGFR and WNT5A genes which may be associated with breast cancer progression and metastasis.

摘要…………………………………………………………………………………….i
Abstract………………………………………………………………………...……...ii
致謝…………………………………………………………………………………...iii
目錄………………………………………………………………………………..….vi
介紹…………………………………………………………………………….……...1
1乳癌（Breast cancer）…………………………………………………………..….1
1.1乳癌的發生及進展……………………………………………………………..…1
1.2乳癌轉移（Breast cancer metastasis）………………………………………..….2
1.3 腫瘤微環境（Tumor microenvironment）……………………………..………..3
1.4乳癌治療 ……………………………………………………………………..…..4
2.嗎啡（Morphine）對癌症的影響 …………………………………………..…..5
3. K他命（Ketamine）對癌症的影響 ………………………………………………6
4.表觀遺傳學調控基因表現 …………………………………………………………7
材料與方法 ………………………………………………………………………..11
結果 ………………………………………………………………………..……14
K他命或嗎啡促進乳癌腫瘤體積和重量增加 ……………………….………….14
K他命促進乳癌的肺轉移 …………………………………………………….….14
K他命和嗎啡不影響 EO771細胞的增生但促進遷移/侵襲………………...........15
K他命或嗎啡增加與乳癌發生相關的基因表現 ……………………………..……16
MiR-27b-3p促進乳癌遷移/侵襲……………………………………………………17
利用全基因定序分析受K他命影響的基因……………………………………….18
分析受K他命影響的生物信號、路徑及基因表現……………………………….19
K他命成癮促進乳癌轉移過程中BMP5、EGFR、WNT5A基因的大量表現……………………………………………………………………………………..20
探討K他命是否調控BMP5、WNT5A、EGFR基因表現的轉錄因子……..…..21
K他命成癮增加腫瘤微環境相關基因的表現……………………………………..22
討論………………………………………………………………………………......23
附圖…………………………………………………………………………………..26
圖一、K他命或嗎啡成癮小鼠的乳癌腫瘤模型 …………………………………..26
圖二、K他命或嗎啡成癮促進乳腺腫瘤生長……………………………………..29
圖三、K他命成癮促進乳腺腫瘤轉移……………………………………………..30
圖四、測定K他命或嗎啡處理後EO771細胞增殖及侵襲………………………33
圖五、K他命成癮小鼠腫瘤中乳癌相關基因表現量 ……………………………..35
圖六、嗎啡成癮小鼠腫瘤中乳癌相關基因表現量………………………………..36
圖七、小鼠腫瘤中miR-27b-3p的表現量…………………………………………38
圖八、大量表現miR-27b-3p對E0771細胞增殖和侵襲的影響…………………39
圖九、送RNA-seq的RNA樣品配製………………………………………… …..40
圖十、腫瘤基因分析之PCA及Heatmap 圖……………………………………...42
圖十一、腫瘤中大量表現的基因之KEGG及GO-term圖………………………45
圖十二、分析K他命成癮組大量表現的基因及調控機制………………………50
圖十三、分析K他命組與腫瘤微環境相關的基因………………………………51
圖十四、分析BMP5、EGFR、WNT5A啟動子上的H3K27me3組蛋白標記……………………………………………………………………………………..53
圖十五、K他命成癮促進乳癌進展的示意圖……………………………………..54
表格…………………………………………………………………………………..55
參考資料……………………………………………………………………………..56

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