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研究生:李明澤
研究生(外文):Ming-TseLee
論文名稱:CD44促進食道癌細胞表面纖連蛋白內吞而抑制經由纖連蛋白組裝所導致的癌症轉移
論文名稱(外文):The CD44-promoted Fibronectin Endocytosis Prevents Pericellular Fibronectin Assembly-mediated Metastasis of Esophageal Squamous Cell Carcinoma Cells
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:130
中文關鍵詞:纖連蛋白CD44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:FibronectinCD44AssemblyEndocytosisSuspanded tumor cellCirculating tumor cellCancer metastasis
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血行性癌細胞(circulating tumor cells)表面纖連蛋白(fibronectin, FN ) 的組裝在與肺臟血管內皮細胞結合機制中扮演重要的角色。不具穿膜區域的胞外基質(extracellular matrix)中的一員FN需透過與細胞表面穿膜蛋白受器結合來促進FN的組裝,但血行性癌細胞膜上的FN受器尚未被研究。目前我們實驗室已發現鈉氫離子交換蛋白(Sodium/hydrogen exchanger;NHE)可扮演此受器的角色而促進FN的組裝與癌細胞肺轉移。而有文獻也指出,另一細胞表面穿膜蛋白CD44也會與FN結合。CD44 的數個exons中只variant exon 3 (V3)接有heparan sulfate glycosaminoglycans,而FN又含有數個heparin binding sites,此事實合理化了這兩分子的結合,但CD44與癌細胞轉移能力的關係卻極具爭議性。我們實驗室過去發現低轉移能力之人類乳癌及食道癌細胞中CD44扮演抑制轉移的角色。且在臨床上,含variant exon 3的isoforms (V3-CD44)在低轉移程度的癌症病人組織中表現較多。文獻又指出CD44可透過lipid raft被細胞內吞。因此,我們假設CD44可能利用v3與FN結合並藉由lipid rafts進行內吞來抑制NHE上FN的組裝並減少肺轉移。食道癌在台灣的發病率連年攀升,因此我們以食道癌為研究模式。首先,我們發現食道癌細胞表面組裝的程度主要受到FN內吞的影響而非自環境中攝取FN的能力。接著我們發現v3-CD44在食道癌細胞中的確可藉著與FN結合而促進整個V3-CD44/FN複合體在lipid raft區域內內吞入細胞中。另外,由外圍移位至lipid raft區域的NHE會促進含NHE、v3-CD44、高分子量FN之巨大複合體被食道癌細胞經由依賴V3-CD44途徑所內吞,並減少表面FN組裝。本實驗室的研究已知Rho A可以負調控FN組裝,我們接著發現因v3-CD44/FN的共同內吞而受抑制的細胞表面FN組裝可被Rho A下游之Rho kinase (ROK)蛋白所促進。最後,我們更發現v3-CD44可在Lipid raft以外區域扮演FN組裝之細胞表面受器。這些結果提供有力的證據來支持v3-CD44可利用與FN的結合與有lipid raft參與的內吞,而抑制FN組裝的假說。本論文部分揭開了懸浮(血行性)食道癌癌細胞調控細胞表面組裝FN的訊息傳遞分子機制,提供了未來遏止癌症轉移的可能治療標靶分子,且可能為食道癌癌症病人因延長壽命而帶來一線治癒的曙光。
The pericellular fibronctin (FN) assembled on circulating tumor cells (CTCs) plays an important role in mediating binding of CTCs to the lung endothelia. In order to be assembled on suspended tumor cell surfaces, FN, one of non-transmembrane extracellular matrix components, must first bind to surface transmembrane receptor(s). However, not any evidence has been provided in the studies of the surface transmembrane receptor(s) on suspended tumor cells for FN. We have preliminarily found that Sodium/hydrogen exchanger (NHE) may serve as such a FN receptor in promoting cell surface FN assembly, leading to cancer metastasis in the lungs. Interestingly, CD44, another cell surface transmembrane protein, is also capable of binding to FN. Among various exons of CD44, only variant exon 3 (V3) is glycosylated with heparan sulfate glycosaminoglycans, a potential FN-binding site within CD44 to bind to heparin binding sites within FN. Nevertheless, the relationship between CD44 expression and cancer metastasis is relatively controversial. Our preliminary results indicate a role of CD44 expressions of human breast cancer and esophageal squamous carcinoma cells (ESCCs) with low metastatic abilities in suppressing metastases. Clinically, it has also been found that isoforms harboring V3 (V3-CD44s) are highly expressed in cancer tissues of those cancer patients who have less metastatic complications and better prognosis. Moreover, it has been known that CD44 within lipid rafts may be endocytosed, leading us to the hypothesis that V3-CD44s suppress cancer metastasis via promoting lipid raft-engaged endocytosis of V3-CD44s/FN complexes and thus inhibiting NHE-mediated pericellular FN assembly on cancer cell surfaces. Since the morbidity and mortality of ESCC in Taiwan recently have been climbing high, we thus employ ESCC as our main study model. We first demonstrated that it is the ability of FN endocytosis, but not that of the FN-uptaking, that regulates pericellular FN assembly on ESCCs. Next, we showed that the V3-CD44 was endocytosed together with surface FN being formed as a large complex within lipid rafts. Moreover, we found that the translocation of NHE into lipid rafts may promote a V3-CD44-mediated endocytosis of large complexes including NHE, V3-CD44, and polymeric FN, leading to the reduction of the pericellular FN assembly of ESCCs. Preliminarily, we found that the activity of RhoA negatively regulates pericellular FN assembly of breast cancer cells. Here, we showed that a reduction of pericellular FN assembly via endocytosis of V3-CD44/FN complexes was provoked by Rho kinases (ROKs), the direct downstream effectors of RhoA. Finally, we found that, once located outside lipid rafts, V3-CD44 may serve as another cell surface receptor in promoting pericellular FN assembly. These results strongly support our hypothesis that V3-CD44 suppresses pericelllular FN assembly of ESCCs via complexing with FN within lipid rafts and promoting endocytosis of the V3-CD44/FN complexes. This thesis partially unveils the signaling regulatory mechanism for pericellular FN assembly of suspended ESCCs, provides candidate target molecules for therapeutics to impede cancer metastasis, and sheds lights on curing ESCC patients even in late stages by prolonging patients’ survivals.
摘要 I
Abstract II
誌謝 IV
目錄 V
圖目錄 VII
附圖表目錄 VIII
縮寫表 IX
第一章 緒論 1
癌症轉移 1
食道癌 3
FN與癌症轉移 5
CD44與癌症轉移 9
Lipid raft 與內吞 11
Rho GTPase 與CD44細胞表面表現 13
研究動機 14
第二章 實驗材料與方法 16
細胞繼代培養 16
DNA質體製備 16
電穿孔細胞轉染 17
慢病毒(lentivirus)感染細胞轉染 17
西方墨點法 18
FITC conjugated FN 製作 18
Biotinylated-FN 製備 19
V3-CD44-pcDNA質體構築 19
細胞RNA萃取,RT-PCR、v3-CD44 PCR與洋菜凝膠電泳 20
FITC-FN內吞實驗 22
Biotinylated-FN 攝取實驗 23
FITC-FN 組裝實驗 24
Fibronectin Free Serum (FFS)製備 24
細胞表面CD44免疫螢光染色 25
共軛焦顯微鏡觀測 26
細胞總CD44 免疫螢光染色 26
細胞CD44內吞實驗 27
FN-CD44 共同沉澱(Co-precipitation)實驗 28
FN-CD44 共位實驗 29
抑制劑處理 31
第三章 實驗結果 32
食道癌細胞CE81T對於FN內吞能力與FN在細胞表面組裝能力呈現負面相關性 32
食道癌細胞CE81 FNlow表現較CE81 FNhigh多的v3-CD44 33
V3-CD44促進細胞對於FN的內吞而降低其在表面的組裝 35
FN可與食道癌細胞表面的V3-CD44結合 37
V3-CD44可與FN在細胞表面形成複合物而一起被內吞 38
V3-CD44/FN的內吞機制需要lipid raft的參與 39
由外圍移動至lipid raft區域的NHE會促進含NHE、v3-CD44、高分子量FN之巨大複合體被食道癌細胞經由依賴V3-CD44途徑所內吞 40
因v3-CD44/FN的共同內吞而受抑制的細胞表面FN組裝可被Rho kinase (ROK)所促進 44
v3-CD44可在Lipid raft以外區域扮演FN組裝之細胞表面受器 47
第四章 討論 49
CE81 FNhigh細胞與CE81 FN細胞的v3-CD44 mRNA比較 49
CE81 FNhigh細胞之總CD44量多於CE81 FNlow細胞 49
CD44的FN結合位在Variant exon 3尚須證實 50
懸浮狀態細胞之生理現象常異於貼附狀態細胞 50
Lipid raft與CD44的關係需要更多實驗證實 51
Rho A藉由v3-CD44調控FN組裝的假設尚須證實 51
Y-27632可能藉由促進v3-CD44表現且抑制其移至lipid raft進行內吞 52
第五章 結論 54
參考文獻 55
實驗表圖 64
圖1 FN內吞能力決定CE81T細胞的FN表面組裝量 66
圖2 CE81 FN low細胞表現較多V3-CD44 69
圖3 低纖連蛋白組裝細胞表現較多V3-CD4與mRNA,且表現較少表面總CD44 72
圖4 利用RNAi技術抑制CD44的表現 74
圖5 v3-CD44的表現因轉染v3-CD44基因而增加 76
圖6 v3-CD44參與細胞表面之FN組裝的負向調控 79
圖7 v3-CD44參與FN組裝的負向調控 82
圖8 內吞FN與V3-CD44含有高度的共位現象 83
圖9 外源性FN與細胞之v3-CD44有結合作用。 84
圖10 MβCD處理減少Lipid raft表現量 86
圖11 MβCD處理減少FN內吞且增加細胞表面FN組裝 88
圖12 MβCD處理減少v3-CD44內吞 90
圖13 MβCD處理促進表面v3-CD44表現 93
圖14 MβCD處理抑制v3-CD44與FN的共同內吞機制 95
圖15 EIPA可促進CE81細胞之FN內吞 97
圖16 EIPA處理促進v3-CD44內吞 99
圖17 EIPA處理抑制v3-CD44表面表現 101
圖18 EIPA可促進v3-CD44所參與的FN內吞機制 105
圖19 EIPA可促進細胞攝取外源性FN 106
圖20 EIPA可促進v3-CD44之表達 107
圖21 Y-27632可調控CE81細胞之FN內吞與組裝 109
圖22 Y-27632 促進細胞表面v3-CD44的表現 112
圖23 Y-27632可抑制v3-CD44的內吞,但並非藉由抑制lipid raft表現 115
圖24 Y-27632使細胞表面v3-CD44與FN之共位增加 118
圖25 MβCD處理促進細胞表面v3-CD44與FN之共位現象 121

附表圖 122
附圖表1 我們對於v3-CD44促進FN內吞並抑制表面組裝的假設 122
附圖表2 人類CD44 cDNA序列 123
附圖表3 過量表現之v3-CD44序列 126
附圖表4 pcDNA 質體的map 128
附圖表5 pOTB7質體的map 129

自述 130

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