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系統識別號 U0026-2108201314465600
論文名稱(中文) 半乳糖凝集素1誘發的細胞自噬作用可以促進肝癌細胞的化學抗性
論文名稱(英文) Galectin-1-induced autophagy facilitates chemoresistance of hepatocellular carcinoma
校院名稱 成功大學
系所名稱(中) 微生物及免疫學研究所
系所名稱(英) Department of Microbiology & Immunology
學年度 101
學期 2
出版年 102
研究生(中文) 蘇育琦
研究生(英文) Yu-Chi Su
電子信箱 saprinna2004@hotmail.com.tw
學號 S46001066
學位類別 碩士
語文別 中文
論文頁數 84頁
口試委員 指導教授-張志鵬
共同指導教授-林以行
口試委員-林秋烽
口試委員-黃國珍
中文關鍵字 肝癌  化學抗性  腫瘤微環境  半乳糖凝集素-1  細胞自噬 
英文關鍵字 Hepatocellular carcinoma  Chemoresistance  Tumor microenvironment  Galectin-1  Autophagy 
學科別分類
中文摘要 肝癌在台灣是最常見的癌症之ㄧ,其盛行率居高不下。雖然現今化學藥物是做為治療肝癌病患的首要選擇,但隨之衍生的化學抗性時常導致臨床治療失敗。截至目前,導致肝癌產生化學抗性的主要機制尚未釐清。根據先前文獻指出在許多癌症中,腫瘤微環境中某些物質和細胞自噬作用 (autophagy) 可提供化學抗性並幫助癌細胞生長。然而已被鑑定出腫瘤微環境中何種物質可誘發細胞自噬作用並提供化學抗性還是少數。半乳糖凝集素-1 (galectin-1) 可與β半乳糖 (β-galactoside) 結合並屬於外源凝集素 (lectin) 之ㄧ,於肝癌病患中表現量較高且可藉由調控癌細胞貼附、轉移和增生進而幫助癌細胞生長。對於半乳糖凝集素-1在肝癌細胞產生化學抗性的角色目前還不清楚。在本論文中我們證明游離態的半乳糖凝集素-1可藉由誘發細胞自噬流動作用 (autophagic flux) 降低化學藥物引起的肝癌細胞死亡。首先我們發現給予化學藥物氟尿嘧啶 (5-Fluorouracil, 5-Fu) 和順鉑 (cisplatin) 可同時造成肝癌細胞凋亡及誘發細胞自噬。先給予游離態的半乳糖凝集素-1可透過抑制AKT-mTOR活性增強化學藥物引起的細胞自噬流動,進而降低肝癌細胞死亡。游離態半乳糖凝集素-1於肝癌細胞中所提供的化學抗性主要透過與β半乳糖結合的活性而非內源性半乳糖凝集素-1所主導。在細胞自噬缺乏的細胞中無法提供游離態半乳糖凝集素-1所引發的化學抗性,這代表半乳糖凝集素-1所誘發的細胞自噬對於提供化學抗性是重要的。此外,我們發現細胞若缺乏細胞自噬作用便無法清除化學藥物所造成的受損粒線體,進而增加粒線體膜電位的流失。然而,半乳糖凝集素-1所誘發的細胞自噬可以標定這些受損的粒線體而降低膜電位流失。總結上述,我們發現大量存在於腫瘤微環境中的半乳糖凝集素-1可藉由誘發細胞自噬流動作用進而清除藥物治療造成的受損粒線體而提供化學抗性。我們的研究提供標定半乳糖凝集素-1可做為肝癌治療的新策略。
英文摘要 Hepatocellular carcinoma (HCC) is one of the most common cancers in Taiwan. Although chemotherapy is the priority treatment for HCC patients, drug resistance often leads to clinical failure. The mechanisms of such chemoresistance in HCC remain to be clarified. Previous studies showed that tumor microenvironment and autophagy may contribute to chemoresistance in many cancers. However, the number of identified autophagy-inducers within tumor microenvironment is still limited. Galectin-1 (Gal-1) is a beta-galactoside binding lectin which is up-regulated in HCC patients and promotes tumor growth by mediating cancer cell adhesion, migration and proliferation. The role of Gal-1 in chemoresistance of HCC is still unclear. In this study, we demonstrated that free-form Gal-1 triggers an autophagic flux to attenuate chemo-drugs-induced haptoma cell death. We showed that chemo-drugs, 5-fluorouracil and cisplatin, can stimulate hepatoma cells undergoing both apoptosis and autophagy. Pretreatment of free form Gal-1 can enhance chemo-drugs-induced autophagic flux through inhibiting AKT-mTOR activities and hence reduce cell death. The free form Gal-1-contributed chemoresistance in HCC requires its beta-galactoside binding activity, but is independent with intrinsic Gal-1 involvement. Autophagy-deficient cells fail to provide the free form Gal-1-induced chemoresistance, indicating that Gal-1-triggered autophagy is crucial for the resistance. Moreover, we found that autophagy deficient cells are not able to remove chemo-drugs-induced damaged mitochondria and lead to an increase in mitochondrial membrane potential (MMP) loss. However, Gal-1-triggered autophagy can target these damaged mitochondria to reduce MMP. In conclusion, we found that Gal-1 which is overexpressed in tumor microenvironment can contribute to chemoresistance by inducing autophagic flux and further eliminate chemo-drugs-induced damaged mitochondria. Our study revealed Gal-1 as a new therapeutic target for HCC treatment.
論文目次 中文摘要 I
Abstract II
總目錄 V
圖目錄 IX
縮引 XI
壹、緒論 1
ㄧ、肝癌成因與治療 1
A.肝癌的成因 1
1.肝炎病毒之慢性感染 1
2.酒精性肝硬化 2
3.非酒精性脂肪性肝炎 2
B.肝癌的治療 3
1.氟尿嘧啶 (5-Fluorouracil, 5-Fu) 3
2.順鉑 (cisplatin) 4
二、化學藥物抗性 4
腫瘤微環境 5
三、半乳糖凝集素-1 7
A.半乳糖凝集素1的調控表現 7
B.半乳糖凝集素1的分佈 7
C.半乳糖凝集素1參與的生理功能 8
D.半乳糖凝集素1參與在腫瘤生長的角色 9
四、細胞自噬 10
A.細胞自噬-雙層膜小體的形成 11
B.細胞自噬的偵測 11
C.細胞自噬參與癌症進展 12
D.細胞自噬與細胞凋亡 13
貳、研究特定目標 15
參、材料與方法 16
ㄧ、材料 16
細胞株與培養 16
菌種與質體 16
細菌培養液 17
抗體 17
試劑 18
塑膠、玻璃製品 23
儀器 23
二、方法 25
A.細胞培養與死亡試驗 25
1.細胞繼代培養 25
2.細胞死亡率測定 25
3.細胞凋亡 (Sub-G1 phase) 測定 26
B.誘發細胞自噬作用之測定 26
1.免疫螢光染色 26
2.西方墨點法 27
C.以Short hairpin RNA (shRNA) 抑制蛋白質表現 27
1.轉型實驗 (Transformation) 27
2.慢病毒 (Lentivirus) 的製備 27
3.慢病毒的濃縮 28
D.粒線體膜電位之測定 28
1.以Rhodamine 123染色 28
2.以JC-1染色 29
E.統計分析 29
肆、實驗結果 30
一、化學藥物所誘發的細胞自噬作用會促進肝癌細胞化學抗性 30
二、外給半乳糖凝集素-1於肝癌細胞誘發細胞自噬作用 30
三、外給半乳糖凝集素-1 可以降低化療藥物所引起的細胞凋亡 32
四、在缺乏內源性半乳糖凝集素-1 的肝癌細胞中外給半乳糖凝集素-1依然存有化學抗性 33
五、半乳糖凝集素-1透過誘發細胞自噬作用來提供肝癌細胞的化學抗性 33
六、抑制細胞自噬作用可導致肝癌細胞中粒線體膜電位下降 34
七、外給半乳糖凝集素-1所誘發的細胞自噬作用可減少化學藥物引發的粒線體膜電位下降現象 34
八、外給半乳糖凝集素-1可透過誘發細胞自噬小體 (autophagosome) 來清除受損的粒線體 35
伍、討論 36
一、腫瘤微環境誘發細胞自噬 36
A.藥物誘發的細胞自噬 36
B.半乳糖凝集素1誘發的細胞自噬 36
C.半乳糖凝集素1合併化學藥物所誘發的增強性細胞自噬 37
二、半乳糖凝集素1參與腫瘤發展 38
A.內源性與游離態半乳糖凝集素1之差異 38
B.Huh-7與HepG2細胞株內源性半乳糖凝集素1表現量 39
C.化學藥物刺激對於半乳糖凝集素1表現量 40
D.肝腫瘤微環境中半乳糖凝集素1之來源 40
E.半乳糖凝集素1之濃度 41
三、細胞自噬之於化學抗性 41
A.細胞自噬提供之化學抗性 41
B.細胞自噬與粒線體相關之細胞凋亡 42
四、臨床應用 43
陸、結論 44
柒、參考文獻 45
圖 62
附錄 77
作者簡歷 84

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