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研究生：	葉承昀 Yeh, Chen-Yun
論文名稱：	探討c-Met及Lutheran在膀胱癌發展過程的新穎角色 The novel roles of c-Met and Lutheran in bladder cancer formation
指導教授：	劉校生 Liu, Hsiao-Sheng
學位類別：	碩士 Master
系所名稱：	醫學院 - 微生物及免疫學研究所 Department of Microbiology & Immunology
論文出版年：	2005
畢業學年度：	93
語文別：	英文
論文頁數：	67
中文關鍵詞：	基側抗原、貼附能力、肝細胞生長因子、酪胺酸激酶受體
外文關鍵詞：	HGF, laminin, Lutheran, Met
相關次數：	點閱：126 下載：1
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　　Met是肝細胞生長因子(HGF)的受體，也屬於酪胺酸激酶受體(receptor tyrosine kinase)之一，對於調控細胞的生長、移動及死亡都扮演著相當重要的角色。先前的研究發現，HGF/Met所傳遞的訊息對於膀胱癌的發展具有關鍵的影響。本研究主要揭示Met在膀胱癌發展過程中尚未發現的重要影響因子，我們以NIH/3T3細胞建立了一株四環黴素(tetracycline)能夠調控Met基因表現的NIH-Met5細胞株。發現此細胞的Met蛋白在過量表現時，可使Met蛋白在不受HGF刺激下就能自我磷酸化(auto-phosphorylation)。若給予HGF刺激，Met蛋白的磷酸化現象更為明顯。利用酪胺酸激酶微陣列晶片(microarray)篩選與Met相關的基因，結果發現酪胺酸激酶Axl及PDGFR-的基因表現型錄(gene expression profile)與c-Met的一致，顯示兩者與c-Met之表達相關。而在兩株膀胱癌細胞株中也發現在處理HGF後，Axl及PDGFR-蛋白表現也有升高的情況。膀胱癌臨床檢體的組織切片染色(immunohistochemistry)分析中也證實Met過量表現之檢體同時也有Axl及PDGFR-過量表達之情形，而這些病人發生轉移癌的機率也較其他人為高。總而言之，本研究找到兩個基因受Met之調控與膀胱癌之進程有密切的關係，值得深入探討。

　　LU(Lutheran)常出現在上皮細胞的基側抗原(basolateral antigen)。在我們先前建立表現LU的NIH-Lu11細胞株研究發現，在其配合基(ligand)的刺激下，NIH-Lu11細胞於軟膠(soft agar)之生長能力增強，並能透過Erk/RhoA的訊息傳遞影響細胞的貼附力，也發現到RhoA會影響stree fiber的形成。本研究中，於LU蛋白過量表現時能促使NF-kB的活性上升，並能在BALB/c及免疫缺失的NOD-SCID老鼠長出腫瘤，顯示LU為一致癌基因。此外以高度表現LU的膀胱癌細胞株J82及TCCSUP進一步探討LU的功能。本研究中也發現到laminin-10的處理下，細胞的貼附力也上升。但在Erk、p38及RhoA的抑制劑PD98059、SB203580及C3 exoenzyme的處理下，細胞的吸附力會被抑制。以pull-down分析也同樣發現Erk會影響到RhoA的活性。而在處理stress fiber抑制劑cytochalasin B之下，細胞的貼附能力也受到影響，猜測stress fiber與貼附能力有關。這些結果顯示Erk/MAPK、p38、RhoA以及stress fiber均參與細胞之貼附能力。總而言之，本研究證實LU是一個致癌基因，在腫瘤細胞對胞外基(extracellualr matrix) 的吸附能力上扮演重要的角色，並與癌症的進程密切相關。

　Met, the hepatocyte growth factor (HGF) receptor, is a receptor tyrosine kinase (RTK), and plays an important role in regulating cellular proliferation, motility, and apoptosis. Previously studies indicated that HGF/Met signaling might play a critical role in bladder carcinogenesis. To reveal the novel role of Met in the process of tumorigenesis, a NIH/3T3 derivate, NIH-Met5, with c-Met overexpression in an inducible way by tetracycline was established. We found that c-Met was highly auto-phosphorylated without HGF treatment when c-Met was overexpressed. Treatment of HGF could further enhance c-Met phosphorylation via a dose-dependent way. Utilizing microarray analysis, we found the gene expression profile of kinases Axl and PDGFR-are up-regulated. In bladder cancer cell lines, we also found that Axl and PDGFR- were up-regulated by HGF treatment. In immunohistochemistry analysis, cinical specimens demonstrated the co-expression of c-Met, Axl, and PDGFR- positively associated with aggressive biological indicators or tumor metastasis. In summary, we found two c-Met-regulated genes.

　The Lutheran glycoprotein (LU) is a basolateral antigen in diverse epithelial cells. In our previously studies, treatment of laminin-10 on NIH-Lu11, over-expressing LU cells, could promote anchorage-independent growth and enhance cell adhesion through activation of Erk/RhoA signaling pathway, and RhoA induced the stress fiber formation. We found that NIH-Lu11 could induce NF-kB activity after laminin-10 treatment and tumor formation in the BALB/c and immune deficiency NOD-SCID mice, suggesting the oncogenesity of LU. Two bladder cancer cell lines, J82 and TCCSUP, expressing high level of LU were utilized to study the function of LU. The adhesion feature was blocked by Erk/MAPK inhibitor PD98059, p38 inhibitor SB203580 and Rho GTPase inhibitor C3 exoenzyme treatment. In pull-down assay, we showed that RhoA activity was enhanced via Erk-mediated signaling pathway after laminin-10 treatment. After treating cytochalasin B, a stress fiber inhibitor, cell adhesion was suppressed; suggesting stress fiber was involved in adhesion ability. These results demonstrated that all of Erk/MAPK, p38 and RhoA molecular were involved in adhesion ability. In summary, we confirmed that Lu was an oncogene, and plays an important role in mediating the attachment of cancer cells to the extracellular matrix, correlating to the cancer progression.

Abstract (Chinese)											   	      i
Abstract															     iii
Acknowledgments													  v
Contents															  vi
Index of Figure													    viii
Abbreviations														  x
I.	Introduction													  1
II.	Materials and Methods
1.	Bacterial strain and cell lines									  7
2.	Culture medium and condition									  7
3.	Plasmid and preparation										  9
4.	Establishment of a stable cell line harboring exogenous gene		 12
5.	Western blotting												 13
6.	Immunoprecipitation											 16
7.	Tumorigenicity analysis										 17
8.	Promoter activity assay										 18
9.	Cell adhesion assay											 18
10.	 GTPase pull-down assay										 19
11.	 Statistical analysis											 21
III.	Results															     
1.	Establishment of an inducible cell line stably expressing 
exogenous c-Met gene										 22
2.	The expression and phosphorylation of c-Met in NIH/3T3
 	and NIH-met5 cell lines										 22
3.	The relation of c-Met with Axl and PDGFR-					
4.	The effect of NIH/3T3 cell overexpressing LU on tumor 
formation in the presence or absence of LN-10					 24
5.	The involvement of NF-kB signaling LN/LU-mediated cell 
adhesion		     											 25
6.	The involvement of Erk, p38 and RhoA in LN/LU induced 
cell adhesion											 		 25
7.	The involvement of stress fiber in LN/LU related cell adhesion 
by inhibitor cytochalasin B									 27
8.	The involvement of integrin in LN-10-induced cell adhesion  
in bladder cancer TCCSUP and J82 cells						 27	
IV.	Discussion													 28
V.	References													 34
VI.	About of author												 67








Figure list
Figure 1. Establishment of a stable cell line NIH-Met5 expressing 
inducible Met											 	47
Figure 2. Phosphorylation of c-Met in NIH/3T3 and NIH-Met5 cell 
lines with or without HGF									48
Figure 3. The expression levels of c-Met protein in NIH-Met5 cells 		
in the presence of various concentration of tetracycline		50
Figure 4. The expression levels of Axl and PDGFR- in NIH/3T3 
and NIH-Met5 cells with or without doxycycline and 
tetracycline treatment										51
Figure 5. The expression levels of c-Met, Axl and PDGFR- in 
UB09, UB40 and UB47 bladder cancer cell lines				53
Figure 6. The effect of HGF on the expression levels of Axl and 
PDGFR- in UB09, UB40 and UB47 bladder cancer
cell lines													54
Figure 7. The effect of LU in NIH/3T3 cells on tumor formation of
BALB/c mice with or without LN-10 pre-treatment			55
Figure 8. The effect of LU in NIH/3T3 cells on tumor formation of
NOD-SCID mice with or without LN-10 pre-treatment		56
Figure 9. The effect of Lutheran-laminin on NFB activity				57
Figure 10. The effect of signaling pathway blockers PD98059, SB203580 
and SP600125 on cell adhesion bladder cancer of J82 and 
TCCSUP cells												58
Figure 11. The effect signaling pathway blockers SB203580 and 
SP600125 on cell adhesion of NIH/3T3 and NIH-Lu11 cells	60
Figure 12. The effect of Erk, p38 and JNK on RhoA and Rac1 activity in
bladder cancer cells J82 and TCCSUP after LN-10 treatment	61
Figure 13. The effect of RhoA activity inhibitor C3 exoenzyme on the
adhesion of bladder cancer cells J82 and TCCSUP			62
Figure 14. The effect of actin polymerization inhibitor CytoB on the
adhesion in NIH-Lu11 cells									63
Figure 15. The effect of integrin on the adhesion in bladder cancer 
cells J82 and TCCSUP										64
Figure 16. Hypothesis for up-regulation of Axl and PDGFR- via 
c-Met activation											65
Figure 17. Model of Lutheran-laminin and integrin mediated cell 
adhesion during bladder tumorigenesis						66
                                    

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張心玫。受Ha-ras調控之基因Lutheran blood antigen在人類膀胱致癌化過程之特性研究。成功大學碩士論文，民93。

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