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研究生:徐玉真
研究生(外文):Yu-Chen Hsu
論文名稱:利用基因剔除小鼠探討Hepsin的生理功能
論文名稱(外文):Investigation of the physiological functions of Hepsin using gene knockout mice
指導教授:林淑華林淑華引用關係
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:170
中文關鍵詞:穿膜絲胺酸蛋白酶腫瘤細胞轉移間隙接合分子肝細胞生長因子老鼠模型
外文關鍵詞:serine proteasemetastasisgap junctionhepatocyte growth factormouse model
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Hepsin為第二型穿膜絲胺酸蛋白酶,以肝臟細胞的表現量最多。相關文獻指出,Hepsin可能參與肝細胞發育、受精卵著床、血液凝固機轉等過程,但分子機制尚不明確。此外Hepsin在多種癌細胞株中大量表現,尤以前列腺癌最為明顯,除可成為癌細胞的生物標記外,許多證據顯示Hepsin 可能參與癌細胞的生長與轉移,但調控方式仍不清楚。至於hepsin基因剔除小鼠因無明顯生理異常,故Hepsin生理功能尚待研究。
為探討Hepsin蛋白的生理功能,實驗室先前研究發現,進行脾臟內植入黑色素瘤細胞的癌轉移實驗,hepsin基因剔除(KO)小鼠腫瘤細胞轉移至肝臟的聚落數明顯多於野生型(WT)小鼠,且存活率亦降低。我們根據腫瘤細胞發生轉移的過程與影響腫瘤細胞聚落形成的相關原因設計實驗,逐步排除了hepsin基因剔除小鼠可能的異常。同時,經由不同時間點的觀察,發現自脾臟內植入的黑色素瘤細胞或不同直徑的綠色螢光微球體均易留滯於hepsin基因剔除小鼠肝組織。經過穿透式電子顯微鏡及多光子活體內顯微鏡(multiphoton intravital microscope)觀察後,推測易留滯情形是由於hepsin基因剔除小鼠的肝細胞體積變大,造成血管竇直徑較野生型窄所造成。
根據目前實驗結果推測,hepsin基因剔除小鼠肝細胞體積較大,可能是由於體內缺乏Hepsin蛋白活化pro-HGF為肝細胞生長因子,使肝細胞表面間隙接合分子(gap junction)的組成蛋白Connexin 26 (Cx26)、Cx32代謝減緩後,異常堆積所造成。實驗除證明(1)hepsin基因剔除小鼠血清及肝組織中的肝細胞生長因子濃度及肝細胞生長因子受體c-met磷酸化程度均較野生型小鼠低外,也發現(2)hepsin基因剔除小鼠肝組織的Cx26、Cx32蛋白表現量及傳遞功能均較野生型好,(3) Cx26、Cx32蛋白過量表現的肝細胞株體積會變大,及(4)投予hepsin基因剔除小鼠肝細胞生長因子或投予野生型小鼠肝細胞生長因子拮抗劑NK4均能動態調節所觀察之現象。
根據肝細胞生長因子在橫膈膜發育過程十分重要,而hepsin基因剔除小鼠體內的肝細胞生長因子又濃度偏低,實驗也觀察到hepsin基因剔除小鼠橫膈膜發育異常,且導致肝臟往胸腔擠壓,影響肺功能。另外,由於肝細胞表面Cx26、Cx32蛋白表現增加,hepsin基因剔除小鼠在分離初代肝細胞時(EGTA/collagenase perfusion procedure),細胞存活率及收得活細胞數均較野生型低的現象,可經抑制肝細胞過量表現的間隙接合分子功能,有效提升小鼠初代肝細胞分離後的存活率。
總結實驗結果具有以下重要性:(1)了解肝臟內源性Hepsin蛋白的生理功能與維持肝臟結構或體內肝細胞生長因子濃度的重要性,(2)提供生物體內Hepsin蛋白可活化pro-HGF為肝細胞生長因子的證據,(3)利用活體小鼠,直接提供器官微血管過密或肝臟血管竇過窄,會增加體循環血流中的腫瘤細胞留滯於組織器官的直接模型,且該現象能被動態調節,(4)過去文獻多偏重於Hepsin蛋白與促進癌細胞生長與轉移的關係,甚至多在探討以Hepsin抗體抑制癌轉移的可能應用,而忽略了Hepsin蛋白的生理功能;實驗證明,投予Hepsin抗體可能反而會促進腫瘤細胞轉移至肝臟的風險,需進一步釐清Hepsin蛋白各作用功能區及選擇更適合的抗體以供治療應用。


Hepsin, a type II transmembrane serine protease, was indicated involve in hepatocyte growth, blastocyst hatching and blood coagulation pathway. Since there is no obvious abnormality in hepsin-deficient mice, the physiological functions of Hepsin are still unknown. It has also been reported that the overexpression of Hepsin in many cancer cell lines, especially in prostate cancer. Accordindingly, beside be concerned as a biomarker in cancer, many evidences show that Hepsin may play roles in tumor proliferation and metastasis, but the mechanism is not clear so far.
To evaluate the physiological functions of Hepsin, we challenged the tumor metastasis experiment in the hepsin knockout (KO) mice and found that the isogenic tumor cells colonized more efficiently to livers in the KO mice than that in the WT mice.To investigate this mechanism, we used intrasplenic injection and time course tracing strategies showed that both melanoma cells and the different sizes of fluorescent microbeads were more preferentially trapped in hepsin KO livers. With observation through transmission electron microscope and multiphoton intravital microscope, our results showed that the preferential retention of the tumor cells in the KO mice liver is due to the altered hepatic sinusoidal architecture tortured by the enlarged hepatocytes.
To delineate the mechanism responsible for the change of hepacyte sizes, we found the hepsin KO liver had increased Connexin proteins and the increased gap junctions are associated with changes of hepatocyte size. Further studies shown that hepatocyte growth factor (HGF) was associated with the expression level of Connexin proteins and the KO mice had decreased HGF in the liver microcirculation as well as in liver extracts. These observations demonstrate that hepsin involves in liver metastasis by regulating the diameter of the sinusoids and the volume of hepatocytes through its influence on HGF.
Our study provides evidence showing for the first time the relationships between hepsin and HGF/SF in vivo. We also provide a direct evidence of the relationship between successful tumor metastasis and the architecture of target organs. Our findings suggest the application of hepsin protein can be potential therapeutic approach to remission of the liver metastasis.


口試委員會審定書 I
誌謝 II
中文摘要 III
英文摘要 V
縮寫表 VII
第一章 緒論 1
1.1 HEPSIN 1
1.1.1 Hepsin基因與蛋白結構 1
1.1.2 Hepsin組織分佈與預測功能 2
1.1.3 Hepsin病理功能 3
1.2腫瘤轉移 4
1.2.1 腫瘤細胞轉移過程 5
1.2.2腫瘤細胞轉移理論演進與相關機制 5
1.3 肝臟結構與組成細胞 7
1.3.1肝臟組織結構與循環 7
1.3.2肝臟實質細胞及功能 8
1.3.3肝臟非實質細胞及功能 9
1.4 肝細胞縫隙連接分子 (GAP JUNCTIONAL PROTEINS) 10
1.4.1 接合分子蛋白 10
1.4.2 Connexin蛋白結構、connexon組成 11
1.4.3 Connexin功能與疾病關係 12
1.5 肝細胞生長因子 (HEPATOCYTE GROWTH FACTOR, HGF) 13
1.5.1 肝細胞生長因子結構及活化 13
1.5.2 肝細胞生長因子受器及下游訊息傳遞 15
1.5.3 肝細胞生長因子功能 15
1.6 論文研究動機與實驗策略 17
第二章 實驗材料與方法 19
2.1 實驗動物 19
2.2 活體小鼠內腫瘤細胞癌轉移及生長實驗 19
2.2.1腫瘤細胞培養 19
2.2.2小鼠脾臟內植入腫瘤細胞轉移實驗 19
2.2.3小鼠尾靜脈植入腫瘤細胞轉移實驗 20
2.2.4小鼠肝臟植入腫瘤細胞生長實驗 20
2.3組織病理學及組織免疫染色 20
2.3.1組織檢體處理及切片 20
2.3.2石臘切片的組織染色 (Hematoxylin and Eosin stain) 21
2.3.3石臘切片的免疫組織化學 (immunohistochemistry)染色 21
2.3.4冷凍切片的免疫組織螢光 (immunofluorescence)染色 22
2.4小鼠肝臟表現外源性蛋白 23
2.4.1 表現質體構築 23
2.4.2 Hydrohynamic DNA植入法 23
2.5 HEPSIN重組蛋白表現與純化 24
2.5.1 Hepsin重組蛋白表現質體構築 24
2.5.3 Hepsin膜外區重組蛋白穩定表現細胞株大量表現系統 25
2.5.4 Hepsin重組蛋白純化 26
2.5.5 Hepsin膜外區重組蛋白身分鑑定 26
2.5.6 西方墨點法 27
2.5.7 Hepsin膜外區重組蛋白活性測試 27
2.5.8 蛋白質膠體電泳膠片銀染色 28
2.6 抗HEPSIN蛋白單株抗體製備與抑制小鼠內源性HEPSIN蛋白實驗 28
2.6.1 DNA疫苗免疫法 (DNA vaccine) 28
2.6.2 Hepsin膜外區重組蛋白免疫法 28
2.6.3 利用酵素免疫連結法偵測抗體效價 29
2.6.4 細胞融合 29
2.6.5 抗體單株化 30
2.6.6 單株抗體製備與純化 31
2.6.7以單株抗體抑制小鼠內源性Hepsin蛋白實驗 32
2.6.8單株抗體抑制人類肝細胞株內源性Hepsin蛋白實驗 32
2.7小鼠肝臟各組成細胞分離、培養及相關實驗 33
2.7.1 小鼠肝臟竇間隙內皮細胞分離 33
2.7.2小鼠血管竇內皮細胞免疫螢光染色 34
2.7.3 黑色素瘤細胞與小鼠血管竇內皮細胞黏著作用 35
2.7.4 小鼠初代肝細胞分離及培養 36
2.7.5 小鼠初代肝細胞體積分析 36
2.7.6分離小鼠肝臟白血球 (intrahepatic leukocytes, IHLs)分離 36
2.7.7小鼠肝臟白血球細胞分群分析 37
2.8小鼠肝臟對於循環中腫瘤細胞及微球體 (MICROSPHERE)留滯能力 38
2.8.1 腫瘤細胞螢光標定 38
2.8.2肝組織留滯腫瘤細胞及微球體的數量計數 38
2.8.3肝組織留滯的腫瘤細胞自體凋亡之數量計數 39
2.9電子顯微鏡 39
2.9.1 檢體製備 39
2.9.2穿透式電子顯微鏡觀察、測量小鼠血管竇直徑 (sinusoidal diameter) 40
2.9.3 以穿透式電子顯微鏡觀察、測量小鼠肝細胞所佔面積 40
2.10.1多光子活體內顯微鏡 (MULTIPHOTON INTRAVITAL MICROSCOPE) 40
2.10.1 活體小鼠前處理 40
2.10.2 以多光子活體內顯微鏡測量小鼠血管竇直徑 (sinusoidal diameter) 41
2.10.3 以多光子活體內顯微鏡測量小鼠肝細胞面積 41
2.11小鼠肝臟MRNA及蛋白質表現分析與定量 41
2.11.1 小鼠肝臟RNA萃取 41
2.11.2 反轉錄反應 42
2.11.3 聚合酵素鏈鎖反應 (PCR) 42
2.11.4 即時定量聚合酵素連鎖反應 (Real-Time PCR PCR) 43
2.11.5 小鼠肝臟蛋白萃取 43
2.11.6 以西方墨點法分析小鼠肝臟蛋白 44
2.12間隙接合分子 (GAP JUNCTION) 蛋白相關功能分析 44
2.12.1小鼠肝臟間隙接合分子傳遞功能分析 44
2.12.2細胞過量表現間隙接合分子組成蛋白Connexin對細胞體積的影響 45
2.12.3間隙接合分子功能抑制劑對小鼠血管竇直徑、肝細胞體積的影響 46
2.12.4間隙接合分子功能抑制劑對小鼠肝細胞存活率、肝細胞體積的影響 46
2.13 小鼠內源性肝細胞生長因子測量及蛋白功能分析 47
2.13.1小鼠內源性肝細胞生長因子測量 47
2.13.2肝細胞生長因子及肝細胞生長因子拮抗劑NK4對小鼠血管竇直徑的影響 47
2.14 小鼠橫膈膜形態觀察及肺功能分析 48
2.14.1小鼠橫膈膜解剖及形態觀察 48
2.14.2小鼠肺功能分析 48
2.15 數據分析與統計 49
第三章 實驗結果 51
3.1HEPSIN蛋白與黑色素瘤細胞轉移至肝臟的抑制有關 51
3.1.1基因剔除小鼠腫瘤細胞轉移至肝臟的群落數明顯增多 51
3.1.2基因剔除小鼠肝臟表現Hepsin蛋白能減少腫瘤細胞轉移至肝臟 51
3.1.3抑制野生型小鼠內源性Hepsin蛋白能增加腫瘤細胞轉移至肝臟 52
3.1.4循環中的腫瘤細胞在基因剔除小鼠轉移至肝臟較多 52
3.1.5抑制野生型小鼠內源性Hepsin蛋白能增加循環中腫瘤細胞轉移至肝臟 53
3.1.6該現象非黑色素瘤細胞B16F1單一細胞株特有 53
3.1.7提供基因剔除小鼠soluble form Hepsin蛋白無法抑制腫瘤細胞轉移至肝臟 54
3.1.8表現soluble form Hepsin與否不影響腫瘤細胞轉移至肝臟能力 54
3.2 已初步排除促進腫瘤細胞轉移至肝臟的可能原因 55
3.2.1基因剔除小鼠肝臟釋放的細胞趨化素無明顯增加 55
3.2.1腫瘤細胞黏著於基因剔除小鼠內皮細胞能力無明顯增加 55
3.2.2基因剔除小鼠肝臟細胞外間質 (extracellular matrix)量無異常 56
3.2.3 Hepsin蛋白對腫瘤細胞黏著、降解細胞外間質無明顯影響 56
3.2.4 腫瘤細胞於基因剔除小鼠肝臟增生速度無明顯增加 56
3.2.5基因剔除小鼠肝臟對轉移腫瘤細胞清除能力無明顯異常 56
3.3基因剔除小鼠肝臟較易留滯腫瘤細胞 57
3.3.1基因剔除小鼠肝臟留滯的腫瘤細胞較多 57
3.3.2基因剔除小鼠肝臟留滯的腫瘤細胞凋亡比例無異常 58
3.3.3基因剔除小鼠肝臟留滯的螢光微球體較多 58
3.4 HEPSIN蛋白與肝臟血管竇直徑調節有關 59
3.4.1基因剔除小鼠血管竇直徑較窄 59
3.4.2基因剔除小鼠肝臟表現Hepsin蛋白能使血管竇直徑變寬 59
3.4.3抑制野生型小鼠內源性Hepsin蛋白使血管竇直徑變窄 60
3.5 HEPSIN蛋白與肝細胞體積調節有關 60
3.5.1基因剔除小鼠肝臟非實質細胞分佈及數量無異常 60
3.5.2 肝細胞是肝臟中Hepsin蛋白最主要的表現者 60
3.5.3基因剔除小鼠單顆肝細胞面積較大 61
3.5.4基因剔除小鼠肝臟表現Hepsin蛋白能使肝細胞面積變小 61
3.5.5抑制野生型小鼠內源性Hepsin蛋白使肝細胞面積變大 62
3.5.6抑制細胞內源性Hepsin蛋白使肝細胞體積變大 62
3.6 HEPSIN蛋白與肝組織間隙接合分子表現量有關 62
3.6.1基因剔除小鼠肝臟數個調控細胞體積的離子通道分佈及表現量正常 62
3.6.2基因剔除小鼠desmosomes分佈及表現量無明顯異常 63
3.6.3基因剔除小鼠肝臟間隙接合分子較多 63
3.6.4基因剔除小鼠肝臟間隙接合分子傳遞能力較好 63
3.6.5抑制野生型小鼠內源性Hepsin蛋白使肝臟間隙接合分子變多 63
3.6.6抑制細胞內源性Hepsin蛋白使細胞間隙接合分子變多 64
3.7肝組織間隙接合分子與細胞體積調節有關 64
3.7.1過量表現細胞間隙接合分子能使細胞體積變大 64
3.7.2間隙接合分子功能抑制劑能使基因剔除小鼠肝細胞面積變小 65
3.7.3間隙接合分子功能抑制劑能使基因剔除小鼠血管直徑增加 65
3.8肝細胞生長因子經由間隙接合分子調節細胞體積 65
3.8.1基因剔除小鼠體內肝細胞生長因子濃度較低 65
3.8.2抑制野生型小鼠內源性Hepsin蛋白使血清中肝細胞生長因子濃度降低 66
3.8.3投予肝細胞生長因子使基因剔除小鼠血管竇直徑變寬 66
3.8.4投予肝細胞生長因子拮抗劑NK4使野生型小鼠血管竇直徑變窄 67
3.9基因剔除小鼠肝細胞生長因子較少導致其它影響 67
3.9.1基因剔除小鼠橫膈膜發育異常 67
3.9.2基因剔除小鼠肝臟解剖位置偏高 68
3.9.3基因剔除小鼠引發氣管攣縮後氣道阻力及肺順應性異常 68
3.10間隙接合分子過量表現會降低初代肝細胞分離時存活率 68
3.10.1基因剔除小鼠初代肝細胞分離時存活率及收得活細胞數較低 68
3.10.2基因剔除小鼠初代肝細胞分離時存活率能經抑制間隙接合分子提高 69
第四章 討論 71
4.1 HEPSIN蛋白與黑色素瘤細胞轉移至肝臟的抑制關係 71
4.1.1腫瘤細胞癌轉移實驗模型及生成群落的觀察 71
4.1.2 Hepsin與腫瘤細胞轉移至肝臟的關係 73
4.2促進腫瘤細胞轉移至基因剔除小鼠肝臟的可能原因 75
4.2.1已初步排除促進腫瘤細胞轉移的可能原因 75
4.2.2轉移的腫瘤細胞留滯肝組織與聚落生成的關係 76
4.3 HEPSIN蛋白與肝細胞體積調節的關係 77
4.3.1基因剔除小鼠血管竇變窄源自肝細胞體積較大 77
4.3.2已初步排除造成基因剔除小鼠肝細胞變大的可能原因 78
4.3.3肝組織間隙接合分子與細胞體積的關係 79
4.4 HEPSIN蛋白與肝細胞生長因子關係 80
4.4.1基因剔除小鼠體內肝細胞生長因子濃度較低 80
4.4.2細胞生長因子經由間隙接合分子調節細胞體積。 81
4.5基因剔除小鼠肝細胞生長因子較少導致其它影響 82
4.5.1基因剔除小鼠橫膈膜發育異常。 82
4.5.2基因剔除小鼠肝細胞間隙接合分子功能。 83
第五章 實驗結果與展望 85
參考文獻 87
圖 101
表 168

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