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系統識別號 U0026-0812200914190518
論文名稱(中文) 刀豆素A誘導細胞自噬在肝癌治療與急性肝炎的作用
論文名稱(英文) Concanavalin A-induced autophagy in anti-hepatoma therapy and acute hepatitis
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 96
學期 2
出版年 97
研究生(中文) 張志鵬
研究生(英文) Chih-Peng Chang
電子信箱 s5891135@mail.ncku.edu.tw
學號 s5891135
學位類別 博士
語文別 中文
論文頁數 110頁
口試委員 召集委員-賴明德
口試委員-張文粲
口試委員-陶秘華
指導教授-黎煥耀
口試委員-蘇益仁
口試委員-戴明泓
中文關鍵字 急性肝炎  刀豆素  肝癌  細胞自噬  外源凝集素 
英文關鍵字 autophagy  acute hepatitis  Concanavalin A  lectin  hepatoma 
學科別分類
中文摘要 肝癌在台灣一直都是惡性腫瘤死亡的前兩名,但是現在依然沒有有效的治療方法。刀豆素A (Concanavalin A, Con A) 是能與甘露糖 (mannose) 及葡萄糖 (glucose) 結合的外源凝集素 (lectins) ,在本論文中我們探討刀豆素A抗肝癌的作用。在細胞的實驗裡中,刀豆素A可以結合到脾臟細胞與腫瘤細胞上並分別引發細胞的增生與死亡。在原位小鼠肝癌模式裡,由尾靜脈給予刀豆素A,則可以活化T細胞,並以CD8+ T 細胞來抑制小鼠肝腫瘤的生長,同時具免疫記憶可以抵抗相同腫瘤的再度生長。刀豆素A也有直接毒殺腫瘤的作用,在免疫不全小鼠也可以部份抑制肝腫瘤的生長。我們進一步探討刀豆素A造成細胞死亡的機制。刀豆素A藉由clathrin所主導的細胞內吞 (endocytosis) 進入細胞中,與粒線體結合後,會引發包括形成自噬小體 (autophagosome)、溶解酵素 (lysosomal) 活性增加、BNIP3表現與LC3-II蛋白聚集等細胞自噬 (autophagy) 反應,進而造成肝腫瘤細胞的死亡。第三類的PI3K的抑制劑3-methyladenine可以抑制刀豆素A所引起的自噬小體的增加,也抑制其細胞死亡。利用干擾性RNA的作用發現,刀豆素A是透過增加BNIP3蛋白使得LC3-II產生而引發細胞自噬性死亡,但其他的細胞自噬蛋白,如beclin-1與ATG5並不參與。另外過去刀豆素A可以在小鼠誘發急性肝炎,被認為是透過活化NKT與T細胞而造成肝損傷。但刀豆素A會誘導肝細胞自噬反應的產生,使我們重新評估刀豆素A引發小鼠急性肝炎的作用。我們發現在BABL/c小鼠給予20 mg/kg的刀豆素A可以引發急性肝炎,超過此劑量會造成小鼠死亡;但在免疫不全的SCID與SCID/NOD小鼠,30~40 mg/kg的刀豆素A才可以誘發急性肝炎,其肝損傷的變化和BABL/c小鼠類似,不過在SCID與SCID/NOD小鼠的肝臟組織中並沒有淋巴球的浸潤,而細胞激素的變化也不盡相同。在給予刀豆素A之後,我們觀察到肝臟組織中有LC3-II蛋白轉變的細胞自噬反應發生,細胞自噬發生在BABL/c小鼠的時間要比在SCID/NOD小鼠快。刀豆素A在BABL/c小鼠會刺激IFN-的產生,而這些IFN-可以透過增加LC3蛋白的表現量來增強刀豆素A於肝細胞引發的細胞自噬反應。刀豆素A引發的小鼠急性肝炎可以是T細胞依賴性,如在BABL/c小鼠,或是非T細胞依賴性的,如在SCID/NOD小鼠,而在這兩種急性肝炎模式中刀豆素A都會誘導細胞自噬的發生。刀豆素A藉由與細胞膜上甘露糖及葡萄糖等的結合,可以直接引發肝細胞的細胞自噬反應及間接地活化T細胞,這雙重的作用可以抑制腫瘤的生長或引發急性肝炎。刀豆素A誘導細胞自噬的作用對外源凝集素的應用提供了新的機制。
英文摘要 Hepatocellular carcinoma (HCC) is among the top two malignant cancers leading to death in Taiwan. There is no satisfactory therapy for HCC patients. Concanavalin A (Con A), a lectin with mannose and glucose binding specificity, was tested for anti-hepatoma effects. From in vitro observations, Con A was able to bind to splenocytes and tumor cells to induce cell proliferation and cell death, respectively. In an in situ murine hepatoma model, intravenous injection of Con A could inhibit liver tumor nodule formation through the CD8+ T cell-mediated activity, and establish an immune memory to prevent further challenge of the same tumor. Furthermore, the liver tumor growth was also partially inhibited in severe combined immune deficiency mice. The mechanisms of Con A-induced cell death on hepatoma cells were further studied. We found that Con A would be internalized to mitochondria through clathrin-mediated endocytosis to induce autophagic cell death once bound to the hepatoma cells. The characteristics of autophagic vacuoles, lysosomal activity, BNIP3 expression and LC3-II aggregation were observed. The class III PI3K inhibitor, 3-methyladenine, could both inhibit autophagosome formation and cell death induced by Con A. RNA interference studies shown that Con A-induced autophagic cell death on hepatoma cells was mediated through BNIP3 induction following by LC3-II formation whereas beclin-1 and ATG5 were not involved. Furthermore, it is known that Con A-induced acute hepatitis in mice is mediated through activation of NKT and T cells to cause liver damage. The observation of Con A-induced autophagy on hepatocytes made us to re-evaluate the effect of Con A in mice. Con A at 20 mg/kg induced acute hepatitis in BABL/c mice and became lethal when the dose was higher than 20 mg/kg. However in SCID or SCID/NOD mice, Con A could also induce acute hepatitis but needed higher dose than 30 or 40 mg/kg, respectively. The kinetics of acute hepatitis in immunodeficient mice is similar to that of immunocompetent BABL/c mice. No lymphocyte infiltrations were found in the livers of SCID or SCID/NOD mice, and the cytokine productions were different. An autophagy with LC3-II conversion was demonstrated in the liver post Con A injection with a quicker kinetics in BALB/c than in SCID/NOD mice. IFN- produced in BALB/c mice post Con A injection could enhance the autophagy of hepatocytes through the up-regulation of LC3 expression. Con A-induced acute hepatitis can be either T cell-dependent in BABL/c mice or T cell-independent in SCID/NOD mice, but both have an early autophagic induction. Due to the mannose/glucose-specific binding on cell membrane, Con A can cause both autophagic induction on hepatocytes and immunomodulation on T cells to inhibit tumor growth or induce acute hepatitis in mice. Con A-induced autophagy response provides a novel mechanism for the applications of lectins.
論文目次 考試合格証明................................................................................................................I
中文摘要……………………………………………………………………………...II
英文摘要………………………………………………………………………….....IV
誌謝.............................................................................................................................VI
總目錄……………………………………………………………………………..VIII
圖目錄.........................................................................................................................XI
縮寫索引..................................................................................................................XIII
緒論.............................................................................................................................. 1
研究特定目標............................................................................................................ 15
材料與方法………………………………………………………………………… 16
A. 材料
1. 實驗動物.............................................................................................................. 16
2. 細胞株與培養………………………………………………………………….. 16
3. 抗體…………………………………………………………………………….. 16
4. 試劑…………………………………………………………………………….. 19
5. 塑膠、玻璃製品.................................................................................................. 25
6. 儀器…………………………………………………………………………….. 25
B. 方法
1. 細胞株的生長與死亡試驗…………………………………………………….. 27
2. 刀豆素A結合試驗............................................................................................. 27
3. 原位小鼠肝癌模式以及結腸癌細胞肝轉移的小鼠模式…………………….. 27
4. 在實驗小鼠中去除CD4+或CD8+的細胞…………………………………….. 27
5. 細胞轉殖及顯微鏡觀察……………………………………………………….. 28
6. 偵測細胞酸性小體試驗……………………………………………………….. 28
7. 西方墨點法…………………………………………………………………….. 28
8. 以siRNA抑制蛋白質表現……………………………………………………. 29
9. 免疫組織化學染色…………………………………………………………….. 29
10. 小鼠細胞激素(cytokines)的測定……………………………………………… 30
11. 肝癌病人肝臟組織與刀豆素A的結合實驗…………………………………. 30
12. 偵測hypoxia inducing factor-1 alpha (HIF-)的活性………………………… 30
13. 偵測LC3 mRNA的表現……………………………………………………… 30
實驗結果…………………………………………………………………………….32
I. 具有免疫調節功能與細胞毒殺作用的刀豆素A
能夠抑制小鼠肝腫瘤的生長…………………………………………………… 32
1. 刀豆素藉由甘露糖基結合到腫瘤細胞或淋巴細胞,
進而殺死腫瘤細胞或活化淋巴細胞………………………………………….. 32
2. 刀豆素A可以抑制小鼠肝腫瘤的生長………………………………………. 32
3. 刀豆素A活化免疫系統以CD8+淋巴球抑制肝腫瘤的生長,
並產生免疫記憶力抵抗相同腫瘤的再度生長……………………………….. 33
4. 刀豆素A 也能在沒有淋巴球的幫助下抑制小鼠肝腫瘤的生長…………… 33
II. 探討刀豆素A 引發肝腫瘤細胞死亡的機制..................................................... 34
1. 刀豆素A 於肝腫瘤細胞中誘發細胞自噬 (autophagy) 反應......................... 34
2. 細胞自噬的抑制物,3-methyladenine,
可以抑制刀豆素A 所引發的細胞死亡………………………………………. 35
3. 刀豆素A藉細胞內吞作用 (endocytosis)
進入細胞到粒腺體並引發BNIP3所主導的細胞自噬性死亡......................... 35
III. 刀豆素A 誘發小鼠肝炎伴隨細胞自噬的發生……………………………… 37
1. 刀豆素A 可以在免疫不全小鼠中誘發急性肝炎……………………………. 37
2. 比較刀豆素A在BABL/c、SCID或SCID/NOD
小鼠誘發急性肝炎時細胞激素的變化.............................................................. 38
3. 刀豆素A誘發小鼠急性肝損傷伴隨細胞自噬發生………………………….. 38
4. IFN-透過調節LC3表現增強刀豆素A於肝細胞所引發的細胞自噬……... 39
討論………………………………………………………………………………… 41
I. 刀豆素A抑制小鼠肝腫瘤的生長……………………………………………..41
1. 刀豆素A在淋巴球與腫瘤細胞引發不同細胞反應…………………………. 41
2. 刀豆素A應用於肝腫瘤治療………………………………………………….. 42
3. 免疫系統在刀豆素A抑制小鼠肝腫瘤生長的角色…………………………. 43
II. 刀豆素A 誘發的細胞自噬反應………………………………………………. 46
1. 刀豆素A誘發細胞自噬造成腫瘤細胞死亡…………………………………..46
2. 細胞內吞作用、BNIP3與粒腺體在刀豆素A
誘發肝腫瘤細胞死亡的角色………………………………………………….. 47
3. 刀豆素A誘導非典型的細胞自噬反應………………………………………. 49
III. 細胞自噬在刀豆素A 誘發小鼠急性肝損傷的角色………………………… 50
1. 刀豆素A 在BABL/c、SCID和SCID/NOD
小鼠誘發急性肝損傷的比較………………………………………………….. 50
2. 細胞自噬參與刀豆素A 誘發的小鼠急性肝損傷……………………………. 51
3. IFN-調節刀豆素A 於肝細胞所引發的細胞自噬反應……………………... 51
結論………………………………………………………………………………… 53
參考文獻…………………………………………………………………………… 54
圖…………………………………………………………………………………… 69
附錄……………………………………………………………………………….. 102
作者簡歷………………………………………………………………………….. 109

圖目錄
Figure 1. Con A bound to mannose residues of hepatoma cells or lymphocytes and induced cell death or mitogenesis, respectively.

Figure 2. Con A inhibited liver tumor nodule formation in vivo.

Figure 3. Con A is less cytotoxic to hepatocytes in tumor-bearing mice than in naïve mice.

Figure 4. Histopathology of the liver of hepatoma-one-week-long-bearing mice treated with Con A.

Figure 5. Con A-mediated liver tumor nodule inhibition is CD8+ T cell dependent.

Figure 6. Con A prevented the hepatic metastasis of colon cancer cells.

Figure 7. Con A inhibited liver tumor nodule formation in SCID/NOD mice.

Figure 8. Con A induced autophagy in hepatoma cell lines.

Figure 9. Con A induces autophagic flux on hepatocytes.

Figure 10. 3-MA partially blocks the Con A-induced LC3-II conversion and cell death.

Figure 11. Immobilized Con A failed to induce ML-14a cell growth inhibition and LC3-II conversion.

Figure 12. Con A is internalized by endocytosis and targeted to mitochondria to reduce mitochondrial membrane potential.

Figure 13. Autophagy related proteins and BNIP3 regulated the Con A-induced LC3-II conversion and cell death.

Figure 14. Con A induces acute hepatitis in BALB/c, SCID and SCID/NOD mice.

Figure 15. Histology of liver after Con A injection in BALB/c, SCID, and SCID/NOD mice.
Figure 16. Cytokine production after Con A stimulation in BALB/c, SCID and SCID/ NOD mice.

Figure 17. IL-6 and TNF- are not involved in the Con A-induced acute hepatitis in SCID/NOD mice.

Figure 18. Con A binding to hepatic sinusoidal endothelial cells and hepatocytes in BALB/c and SCID/NOD mice.

Figure 19. Con A induced autophagy in the murine liver.

Figure 20. IFN- enhances Con A-induced autophagy on hepatocytes.

Figure 21. Hypothesis : The role of Con A-induced autophagy in anti-hepatoma therapy and acute hepatitis.

附圖一、 Autophagy and inhibitors.

附圖二、 Two major apoptotic pathways in mammalian cells.

附圖三、 The immunofluorescent staining of Con A to human hepatoma tissue.

附圖四、. Oral inoculation with Con A can partially inhibit HCC growth in mice.

附圖五、. Lectin PSA (a), LCA (b), PHA-L(c), and WGA (d) inhibited liver tumor nodule formation in vivo.

附圖六、. HIF-1a induction by Con A in ML-14a cells.
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陳怡安。(2000)。原位肝癌小鼠模式。成功大學微生物暨免疫研究所碩士論文。
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