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研究生:楊依珊
研究生(外文):Yi-ShanYang
論文名稱:FN與NHE2的結合導致多聚體FN所促進的癌症轉移會受到EIPA經由依賴網格蛋白的內吞機制抑制
論文名稱(外文):FN/NHE2 Binding Leads to Polymeric FN-promoted Cancer Metastasis That Is Inhibited by EIPA via Clathrin-dependent Endocytosis
指導教授:鄭宏祺鄭宏祺引用關係
指導教授(外文):Hung-Chi Cheng
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生物化學暨分子生物學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:93
中文關鍵詞:纖連蛋白NHE2組裝內吞懸浮性癌細胞血行性癌細胞癌症轉移
外文關鍵詞:FibronectinNHE2AssemblyEndocytosisSuspanded tumor cellCirculating tumor cellCancer metastasis
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癌症轉移是造成病患死亡率大幅提高的主因。腫瘤細胞的組織微環境呈弱酸性,且一直被認為與癌細胞的惡性程度有高相關性,也促進轉移的發生。其中,細胞調控酸鹼平衡的蛋白中鈉氫離子交換蛋白(Sodium/Hygrogen exchanger;NHE)的確參與癌症的惡化。從過去老師的研究已知表面具有纖連蛋白(Fibronectin;FN)組裝的懸浮性癌細胞會與肺臟內皮細胞黏著而促進肺臟轉移,且實驗室在大鼠乳癌細胞(MTF7)中的研究的確發現NHE2不僅參與纖連蛋白組裝的調控機制,也可能是纖連蛋白在癌細胞懸浮狀態下接受器。為延續探討此可能性,我們發現阻斷NHE2與纖連蛋白的連接可以成功抑制懸浮性癌細胞表面纖連蛋白組裝而減少癌細胞轉移到肺臟的情形。 NHE2乃是透過膜外片段2~4(ECD2~4)與纖連蛋白的第三型重複片段1~6(FN TypeⅢ repeat1-6)連接來促進在癌細胞表面的組裝。使用NHE專一的抑制劑EIPA (5-Ethylisopropyl Amiloride) 會減少癌細胞表面纖連蛋白組裝並不是透過NHE活性來影響,而是促進纖連蛋白內吞進入細胞造成表面組裝的減少。 EIPA乃藉著促使NHE2/纖連蛋白複合體位移至細胞膜脂筏區域造成纖連蛋白一起被內吞進入細胞。我們也觀察到受EIPA導致的NHE2與纖連蛋白內吞走向lysosomal endocytosis pathway,最後與溶酶體(Lysosome)融合而被降解掉。除此之外, 我們確認EIPA所調控的內吞機制是經由網格蛋白所調控。其中除了網格蛋白,NHE的泛素化也可能參與NHE2/纖連蛋白複合體的內吞。另一方面,我們也利用實驗性動物轉移實驗說明網格蛋白對於癌症轉移的確扮演著負調控的角色。綜合以上敘述,我們發現EIPA減少懸浮性癌細胞表面纖連蛋白組裝是透過依賴網格蛋白的內吞機制進而促使NHE2與纖連蛋白一起由膜上脂筏被內吞到細胞內而走向溶酶體內降解的路徑。本論文在癌症轉移分子機制上的研究為癌症病人的治療提供小分子藥物可能的一些新穎標靶蛋白或訊息傳導途徑。
Metastasis has been the leading cause of death for cancer patients. The microenvironment in tumor tissues is more acidic than in normal ones, which has often been highly correlated with cancer malignancy. Sodium-Hydrogen exchanger (NHE), a transmembrane pH regulator, is indeed involved in cancer progression. Pericellular Fibronectins (FN) assembly of suspended cancer cells promotes the adhesion of cancer cells to lung endothelia, leading to lung metastasis. In a rat metastasis model, it has been demonstrated that NHE2 does not only participate in regulating pericellular FN assembly, but also likely serve as a FN receptor on the surfaces of the suspended mammary adenocarcinoma cell line MTF7.To continue investigating this possibility, we showed that blocking the binding between NHE2 and soluble FN significantly impeded the suspended pericellular FN assembly and reduced lung metastasis of cancer cells. Second, third, and fourth extracellular domains of NHE2 (ECDs 2~4) and 1st to 6th FN type Ⅲ repeats (FNⅢ1-6) were responsible for such binding between NHE2 and FN. Using a specific NHE inhibitor 5-Ethylisopropyl Amiloride (EIPA), we found that the suspended pericellular FN assembly was reduced by the enhanced FN endocytosis. EIPA prompted a translocation of NHE2/FN complexes into lipid rafts to facilitate their concomitant endocytosis. This endocytosis led to the lysosomal degradations of both molecules and was found to be clathrin-dependent. In addition, protein ubiquitination was another likely regulatory factor in triggering the endocytosis of NHE2 and FN. We further showed that clathrin indeed played a role in metastatic suppression. In summary, we found that the FN/NHE2 binding led to suspended pericellular FN-promoted cancer metastasis that was inhibited by EIPA via clathrin-dependent endocytosis and lysosomal degradations. Here, our results possibly provide novel cellular proteins or signaling pathways for small drug molecules as cancer metastatic therapeutics to target.
中文摘要 I
Abstract III
誌謝 V
圖表目錄 VIII
附圖表目錄 IX
縮寫表 X
第一章 緒論 1
癌細胞組織微環境的酸化 1
鈉氫離子交換蛋白(Sodium/Hygrogen exchanger;NHE) 2
臟器特異性與癌症轉移(Organ-specific and Cancer Matastasis) 4
纖連蛋白與癌症轉移(Fibronectin;FN and Cancer Metastasis) 5
鈉氫離子交換蛋白可調控懸浮癌細胞表面纖連蛋白的組裝 6
細胞吞噬作用( Endocytosis) 與網格蛋白(Clathrin) 8
泛素化修飾與纖連蛋白組裝的調控(Ubiquitination and FN assembly) 10
研究動機 11
第二章 實驗材料與方法 12
實驗細胞株 12
細胞繼代培養 12
實驗抗體與藥品 13
FITC-FN 製作 14
BioFN製作 14
Fibronectin free serum(FFS)製作 15
西方墨點法 15
考馬斯亮藍染色(Coomassie Brilliant Blue) 16
懸浮細胞藥物處理 17
懸浮細胞免疫螢光染色 17
MBP-FNⅢ1-6結合上細胞表面的染色 18
NHE2與纖連蛋白共位染色 19
蛋白質親和性沉澱實驗 20
慢病毒(lentivirus)抑制細胞蛋白表達 22
細胞吞噬實驗 23
抗NHE2抗體競爭纖連蛋白實驗 24
Sulfo-SBED 蛋白連接實驗 24
NHE 活性測定(NHE acticity) 25
觀察細胞處理EIPA後上清液中不與細胞連接的纖連蛋白(free form FN) 25
動物模式癌症轉移實驗 26
抗NHE2抗體之動物模式實驗性癌症轉移實驗 26
流式細胞儀定量分析(BD FACS Calibur) 27
第三章 結果 28
鈉氫離子交換蛋白NHE2因增強纖連蛋白在癌細胞表面組裝而促進癌細胞轉移至肺臟 28
NHE2 Extracellular domains (ECD)2/3/4可促使纖連蛋白組裝 29
NHE2 與纖連蛋白在大鼠乳癌細胞表面有共位情形 30
抗NHE2 抗體抑制大鼠乳癌細胞表面纖連蛋白組裝與轉移 31
NHE2 Extracellular fragments 2/3/4都與type ⅢFN1-6連接 32
EIPA促使癌細胞內吞纖連蛋白而非阻止其與NHE的連接來減少細胞表面多聚體纖連蛋白的組裝 33
EIPA 減少細胞表面纖連蛋白組裝是透過促進NHE2/纖連蛋白複合體進入脂筏(Lipid raft)而一同被內吞至細胞內 34
EIPA促進纖連蛋白走向lysosomal endocytosis pathway 36
EIPA透過依賴網格蛋白的內吞機制來減少大鼠乳癌細胞表面纖連蛋白的組裝 36
網格蛋白透過內吞作用而減少細胞表面纖連蛋白組裝進而抑制癌症轉移 38
促進泛素化可抑制大鼠乳癌細胞表面纖連蛋白組裝 39
第四章 結論 40
第五章 討論 42
尋找NHE2與纖連蛋白連接的確切接合位(binding site) 42
抗NHE2 抗體的應用 42
NHE2進入細胞後的走向 43
細胞在一般情況下纖連蛋白的內吞並不透過MHE2 44
EIPA透過依賴網格蛋白的內吞機制調控癌細胞表面纖連蛋白的組裝 44
NHE2是否透過泛素化修飾來影響其內吞情形進而調控纖連蛋白的組裝 46
EIPA目前在臨床上的應用 46
第六章 參考文獻 47
第七章 實驗圖表 59
第八章 附圖表 87

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