進階搜尋


下載電子全文  
系統識別號 U0026-0808201021195600
論文名稱(中文) Met基因在肺癌中的變異機制
論文名稱(英文) Alteration Mechanisms of Met Gene in Lung Cancer
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 98
學期 2
出版年 99
研究生(中文) 楊宗瀚
研究生(英文) Tsung-Han Yang
學號 s2697406
學位類別 碩士
語文別 英文
論文頁數 83頁
口試委員 指導教授-王憶卿
口試委員-黃秀芬
口試委員-陳怡榮
口試委員-洪建中
中文關鍵字 非小細胞肺癌  轉錄因子  基因多型性  受體酪胺酸激酶  免疫組織染色 
英文關鍵字 NSCLC  Met  HGF  MACC1  Sp1  IHC  polymorphism  transcriptional regulation 
學科別分類
中文摘要 研究背景及目的: Met 為一細胞膜上的受體酪胺酸激酶,其配體(ligand) 為 hepatocyte growth factor (HGF)。Met 的過度表現與活化參與在許多癌症的惡化與進展中,本實驗室先前研究發現,在141位台灣非小細胞肺癌 (non-small cell lung cancer, NSCLC) 病患中,有高達 76% Met 過度表達的情形。因此,本研究主要目的為透過肺癌細胞以及臨床檢體的相關實驗來探討 Met 基因的變異機制。
研究方法及結果: 在我們實驗室先前的研究當中,已經發現 Met 基因的擴增 (amplification) 比例在台灣 NSCLC 病患很低 (10.5%, 2/19),而且也沒有任何體細胞突變 (somatic mutation) 的情形 (0/148)。雖然本研究進一步發現台灣 NSCLC 病患所特有的一個 Met 基因 N375S 多型性 (polymorphism),但是此基因多型性卻與得到肺癌的風險以及預後無關。因此,我們進一步檢測是否 Met 蛋白層次上有所變異。利用免疫組織染色 (immunohistochemistry, IHC),我們發現 HGF 以及 Met 的過度表現與 Met 的活化態 (p-Met) 呈現正相關性 (P值分別為0.001以及0.046),因而證實了 Met 的過度活化可由其配體 HGF的刺激和 Met 的過度表現所造成。此外,我們還發現 Met 的過度活化可當做腫瘤分期早期 (stage I和II) 病人的預後指標 (P值為0.037)。最近的一篇報導中指出,Metastasis Associated in Colon Cancer 1 (MACC1) 能在大腸癌中大量表現,並且為 Met 基因的一個新穎轉錄因子。因此,我們利用定量 PCR (quantitative reverse transcription polymerase chain reaction, RT-QPCR) 和 IHC 分析肺癌病患 MACC1 的表達量,發現分別有79.8% (99/124) 和 67.1% (49/73) 的肺癌病患其 MACC1 mRNA 以及蛋白有過度表現的情形;此外,病患 MACC1 蛋白表達量與 Met mRNA 的表達量呈現正相關性 (P值為0.036),顯示轉錄因子 MACC1 在肺癌中,有可能參與調控 Met 的表達。我們進一步利用染色質免疫沉澱法 (chromatin immunoprecipitation, ChIP),發現 MACC1 能與 Met promoter 結合。此外,若將肺癌細胞的 MACC1 基因抑制表現 (knock-down),Met mRNA 以及蛋白的表現量也會跟著下降。我們更發現隨著 MACC1 基因的抑制表現,H226Br 肺癌細胞的爬行和侵犯能力都下降了。更重要的是,在已經有淋巴轉移的肺癌病患身上,若其 MACC1 mRNA 過度表達,則病人的總體存活率比 MACC1 mRNA 沒有過度表達的病人還要差 (P值為0.030)。綜合以上的實驗,MACC1 確實在肺癌中能透過轉錄層次的活化調控 Met 的過度表達,並且可能可以促進肺癌細胞轉移的能力而造成病人預後的不佳。文獻更指出,MACC1 必須透過 Met 啟動子 (promoter) 的 Specific protein 1 (Sp1, 另一個能調控 Met 表達的轉錄因子) 結合位才能誘導 Met 啟動子的活性。在我們的研究當中,利用肺癌細胞以及臨床檢體的相關實驗,證實 Sp1 能在肺癌中大量表現,並且能調控 Met 的過度表達;此外,利用免疫沉澱法 (immunoprecipitation),我們發現在肺癌細胞中,MACC1與 Sp1 有蛋白交互作用;更重要的是,以ChIP-QPCR的實驗,我們發現 MACC1 必須要透過與其有交互作用的 Sp1 蛋白,才能與 Met 啟動子上的 Sp1 結合位做結合,進而調控 Met 的表達。因此,Met 的過度表達是由於 MACC1 以及 Sp1 這兩個轉錄因子的大量表現所共同調控造成的。
結論:總結以上實驗,本研究利用了肺癌細胞以及臨床檢體的相關實驗,證實了 HGF-MACC1-Sp1-Met 的訊息傳遞路徑不但能造成腫瘤形成與轉移,還能提供病人預後的一個重要指標。
英文摘要 Background and Purpose: Uncontrolled activation of Met, the tyrosine kinase receptor for hepatocyte growth factor (HGF), is oncogenic and has been implicated in the growth, invasion and metastasis in a variety of tumors. Our previous study showed that 76% (106/148) of lung cancer patients had high Met protein expression. Therefore, the current study aims to investigate the alteration mechanisms of Met in lung cancer cell and clinical models.
Results: In our previous study, rare amplification (10.5%, 2/19) and no somatic mutations (0/148) were found in Taiwanese non-small cell lung cancer (NSCLC) patients. Although there was a racial specific Met N375S polymorphism (14%, 20/141) in Taiwanese NSCLC patients, the current study found that N375S polymorphism was not associated with lung cancer susceptibility and prognosis. Therefore, we further examined the alterations of Met in protein level. Immunohistochemistry (IHC) data showed that both HGF and Met overexpression correlated with Met activation (P=0.001 and P=0.046, respectively), indicating that Met could be over-activated by HGF induction and Met overexpression. In addition, patients of early stage with Met activation showed poor prognosis (P=0.037). Recent report in colon cancer model suggested that metastasis-associated in colon cancer-1 (MACC1) is a novel transcription factor of Met. Using quantitative reverse transcription polymerase chain reaction (RT-QPCR) and IHC, we found that 79.8% (99/124) and 67.1% (49/73) of lung cancer patients showed overexpression of MACC1 mRNA and protein, respectively. In addition, the expression of MACC1 protein correlated with the expression of Met mRNA (P=0.036), suggesting that the transcription factor, MACC1, may positively regulate Met expression in lung cancer. By chromatin immunoprecipitation (ChIP) assay, we found that MACC1 bound Met promoter and knock-down of MACC1 gene decreased Met mRNA and protein levels. Furthermore, knock down of MACC1 gene decreased migration and invasion abilities in H226Br lung cancer cells. Importantly, patients of lymph nodes metastasis with high MACC1 mRNA expression had poorer overall survival than other patients (P=0.030). Collectively, these data indicated that MACC1 induced Met overexpression by positively regulating transcriptional activity of Met gene in lung cancer, which is one of possible mechanisms that MACC1 led to lung cancer metastasis and poor prognosis. A recent study showed that specific protein 1 (Sp1, another known transcription factor of Met) binding site in Met promoter is essential for MACC1-induced Met promoter activity. Our data indicated that Sp1 was also involved in positive regulation of Met expression in lung cancer cell and clinical models. In addition, we found that MACC1 interacted with Sp1 in lung cancer cells by immunoprecipitation assay. Importantly, ChIP-QPCR data indicated that MACC1 bound to Sp1 binding site of Met promoter via Sp1 protein and further regulate Met expression by transcriptional activation. Therefore, MACC1/Sp1 complex positively regulated Met expression via Sp1 site.
Conclusion: Our study provides compelling evidence from clinical and cell models that HGF-MACC1-Sp1-Met axis involves in lung tumorigenesis and poor prognosis.
論文目次 Introduction-------------------------------------------------------------------- 1
I. The clinical significance of lung cancer--------------------------- 1
II. HGF/Met signaling axis----------------------------------------------- 1
(a) General structure of Met and ligand HGF---------------------------- 1
(b) Normal physiological function of Met-------------------------------- 2
(c) HGF-Met downstream signaling--------------------------------------- 3
(d) Met interaction with other receptor families------------------------- 5
III. Transcriptional regulators of Met gene------------------------- 6
IV. Metastasis associated in colon cancer-1 (MACC1)---------- 7
(a) MACC1 protein domains and possible modifications--------------- 7
(b) MACC1 expression in normal and tumor tissues-------------------- 8
(c) The role of MACC1 in colon cancer----------------------------------- 9
V. Dysregulated HGF/Met signaling in cancer------------------ 10
(a) Deregulated “invasive growth” mediated by Met in cancer------ 10
(b) Met and angiogenesis in cancer-------------------------------------- 11
(c) Met, HGF and cancer-------------------------------------------------- 12
VI. The alteration mechanisms of Met gene in cancer-------- 12
(a) Chromosome translocation, amplification and mutation of Met gene----------------------------------------------------------------- 13
(b) Aberrantly transcriptional upregulation of Met in cancer--------- 14
(c) HGF-dependent paracrine and autocarine activation of Met in cancer------------------------------------------------------------------ 15
(d) Abnormal degradation of Met by proteolysis in cancer----------- 16
Study basis and specific aims------------------------------------------ 18
Materials and Methods--------------------------------------------------- 19
I. Study population-------------------------------------------------------- 19
II. Polymorphism assay---------------------------------------------------- 20
III. Immunohistochemistry (IHC) assay---------------------------------- 20
IV. Real-time quantitative polymerase chain reaction (QPCR)-------- 21
V. RNA extraction, quantitative reverse-transcriptase PCR (RT-QPCR) and reverse-transcriptase PCR (RT-PCR) assays---- 22
VI. Cell culture--------------------------------------------------------------- 23
VII. RNAi and transfection-------------------------------------------------- 23
VIII. Western blot-------------------------------------------------------------- 23
IX. Transwell migration and invasion assays---------------------------- 24
X. Analysis of cell proliferation------------------------------------------ 24
XI. Immunoprecipitation (IP)-Western blot analysis-------------------- 25
XII. Chromatin immunoprecipitation (ChIP)-PCR and QPCR assays-------------------------------------------------------- 25
XIII. Statistical analysis------------------------------------------------------- 25
Results-------------------------------------------------------------------------- 27
IN CLINICAL MODEL:
I. The N375S polymorphism of Met gene is not associated with lung cancer susceptibility and prognosis-------------------------------------- 27
II. Met can be activated by HGF overexpression and Met overexpression in lung cancer patients----------------------------- 28
III. MACC1 and Sp1 transcription factors overexpress in lung cancer patients and may positively regulate Met overexpression---- 29
IV. Met and MACC1 as prognostic markers for lung cancer patients--- 31
IN CELL MODEL:
I. MACC1 overexpresses in several lung cancer cell lines-------------- 31
II. Knock-down of MACC1 inhibits the migration and invasion abilities of lung cancer cells----------------------------------------------- 32
III. MACC1 and Sp1 bind at Met promoter containing Sp1 binding site and positively regulate the expression of Met by transcriptional activation in lung cancer cell lines----------------- 32
IV. MACC1 interacts with Met promoter indirectly via Sp1 protein---- 33
Discussion--------------------------------------------------------------------- 35
References--------------------------------------------------------------------- 39
Tables--------------------------------------------------------------------------- 50
Figures-------------------------------------------------------------------------- 63
參考文獻 Abounader, R., Lal, B., Luddy, C., Koe, G., Davidson, B., Rosen, E.M., and Laterra, J. (2002). In vivo targeting of SF/HGF and c-met expression via U1snRNA/ribozymes inhibits glioma growth and angiogenesis and promotes apoptosis. FASEB J 16, 108-110.
Abounader, R., Ranganathan, S., Kim, B.Y., Nichols, C., and Laterra, J. (2001). Signaling pathways in the induction of c-met receptor expression by its ligand scatter factor/hepatocyte growth factor in human glioblastoma. J Neurochem 76, 1497-1508.
Bean, J., Brennan, C., Shih, J.Y., Riely, G., Viale, A., Wang, L., Chitale, D., Motoi, N., Szoke, J., Broderick, S., Balak, M., Chang, W.C., Yu, C.J., Gazdar, A., Pass, H., Rusch, V., Gerald, W., Huang, S.F., Yang, P.C., Miller, V., Ladanyi, M., Yang, C.H., and Pao, W. (2007). MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A 104, 20932-20937.
Benedettini, E., Sholl, L.M., Peyton, M., Reilly, J., Ware, C., Davis, L., Vena, N., Bailey, D., Yeap, B.Y., Fiorentino, M., Ligon, A.H., Pan, B.S., Richon, V., Minna, J.D., Gazdar, A.F., Draetta, G., Bosari, S., Chirieac, L.R., Lutterbach, B., and Loda, M. (2010). Met activation in non-small cell lung cancer is associated with de novo resistance to EGFR inhibitors and the development of brain metastasis. In Am J pathol, pp. 1-9.
Bergstrom, J.D., Westermark, B., and Heldin, N.E. (2000). Epidermal growth factor receptor signaling activates met in human anaplastic thyroid carcinoma cells. Exp Cell Res 259, 293-299.
Bhattacharjee, A., Richards, W.G., Staunton, J., Li, C., Monti, S., Vasa, P., Ladd, C., Beheshti, J., Bueno, R., Gillette, M., Loda, M., Weber, G., Mark, E.J., Lander, E.S., Wong, W., Johnson, B.E., Golub, T.R., Sugarbaker, D.J., and Meyerson, M. (2001). Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98, 13790-13795.
Birchmeier, C., Birchmeier, W., Gherardi, E., and Vande Woude, G.F. (2003). Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4, 915-925.
Birchmeier, C., and Gherardi, E. (1998). Developmental roles of HGF/SF and its receptor, the c-Met tyrosine kinase. Trends Cell Biol 8, 404-410.
Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A., and Birchmeier, C. (1995). Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768-771.
Boccaccio, C., Ando, M., Tamagnone, L., Bardelli, A., Michieli, P., Battistini, C., and Comoglio, P.M. (1998). Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 391, 285-288.
Bottaro, D.P., and Liotta, L.A. (2003). Cancer: Out of air is not out of action. Nature 423, 593-595.
Bussolino, F., Di Renzo, M.F., Ziche, M., Bocchietto, E., Olivero, M., Naldini, L., Gaudino, G., Tamagnone, L., Coffer, A., and Comoglio, P.M. (1992). Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119, 629-641.
Cappuzzo, F., Janne, P.A., Skokan, M., Finocchiaro, G., Rossi, E., Ligorio, C., Zucali, P.A., Terracciano, L., Toschi, L., Roncalli, M., Destro, A., Incarbone, M., Alloisio, M., Santoro, A., and Varella-Garcia, M. (2009a). MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Ann Oncol 20, 298-304.
Cappuzzo, F., Marchetti, A., Skokan, M., Rossi, E., Gajapathy, S., Felicioni, L., Del Grammastro, M., Sciarrotta, M.G., Buttitta, F., Incarbone, M., Toschi, L., Finocchiaro, G., Destro, A., Terracciano, L., Roncalli, M., Alloisio, M., Santoro, A., and Varella-Garcia, M. (2009b). Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol 27, 1667-1674.
Cheng, T.L., Chang, M.Y., Huang, S.Y., Sheu, C.C., Kao, E.L., Cheng, Y.J., and Chong, I.W. (2005). Overexpression of circulating c-met messenger RNA is significantly correlated with nodal stage and early recurrence in non-small cell lung cancer. Chest 128, 1453-1460.
Cipriani, N.A., Abidoye, O.O., Vokes, E., and Salgia, R. (2009). MET as a target for treatment of chest tumors. Lung Cancer 63, 169-179.
Cooper, C.S., Park, M., Blair, D.G., Tainsky, M.A., Huebner, K., Croce, C.M., and Vande Woude, G.F. (1984). Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311, 29-33.
Corso, S., Comoglio, P.M., and Giordano, S. (2005). Cancer therapy: can the challenge be MET? Trends Mol Med 11, 284-292.
Danilkovitch-Miagkova, A., and Zbar, B. (2002). Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. J Clin Invest 109, 863-867.
Day, R.M., Cioce, V., Breckenridge, D., Castagnino, P., and Bottaro, D.P. (1999). Differential signaling by alternative HGF isoforms through c-Met: activation of both MAP kinase and PI 3-kinase pathways is insufficient for mitogenesis. Oncogene 18, 3399-3406.
Department of Health, T.E.Y., Republic of China (2008). General Health Statistics.
Di Renzo, M.F., Olivero, M., Giacomini, A., Porte, H., Chastre, E., Mirossay, L., Nordlinger, B., Bretti, S., Bottardi, S., Giordano, S., Plebani, M., Gespach, C., and Comoglio, P.M. (1995). Overexpression and amplification of the met/HGF receptor gene during the progression of colorectal cancer. Clin Cancer Res 1, 147-154.
Di Renzo, M.F., Olivero, M., Martone, T., Maffe, A., Maggiora, P., Stefani, A.D., Valente, G., Giordano, S., Cortesina, G., and Comoglio, P.M. (2000). Somatic mutations of the MET oncogene are selected during metastatic spread of human HNSC carcinomas. Oncogene 19, 1547-1555.
Eder, J.P., Vande Woude, G.F., Boerner, S.A., and LoRusso, P.M. (2009). Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clin Cancer Res 15, 2207-2214.
Engelman, J.A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J.O., Lindeman, N., Gale, C.M., Zhao, X., Christensen, J., Kosaka, T., Holmes, A.J., Rogers, A.M., Cappuzzo, F., Mok, T., Lee, C., Johnson, B.E., Cantley, L.C., and Janne, P.A. (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316, 1039-1043.
Epstein, J.A., Shapiro, D.N., Cheng, J., Lam, P.Y., and Maas, R.L. (1996). Pax3 modulates expression of the c-Met receptor during limb muscle development. Proc Natl Acad Sci U S A 93, 4213-4218.
Ferracini, R., Olivero, M., Di Renzo, M.F., Martano, M., De Giovanni, C., Nanni, P., Basso, G., Scotlandi, K., Lollini, P.L., and Comoglio, P.M. (1996). Retrogenic expression of the MET proto-oncogene correlates with the invasive phenotype of human rhabdomyosarcomas. Oncogene 12, 1697-1705.
Fischer, O.M., Giordano, S., Comoglio, P.M., and Ullrich, A. (2004). Reactive oxygen species mediate Met receptor transactivation by G protein-coupled receptors and the epidermal growth factor receptor in human carcinoma cells. J Biol Chem 279, 28970-28978.
Follenzi, A., Bakovic, S., Gual, P., Stella, M.C., Longati, P., and Comoglio, P.M. (2000). Cross-talk between the proto-oncogenes Met and Ron. Oncogene 19, 3041-3049.
Furge, K.A., Zhang, Y.W., and Vande Woude, G.F. (2000). Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 19, 5582-5589.
Furlan, A., Vercamer, C., Desbiens, X., and Pourtier, A. (2008). Ets-1 triggers and orchestrates the malignant phenotype of mammary cancer cells within their matrix environment. J Cell Physiol 215, 782-793.
Gambarotta, G., Boccaccio, C., Giordano, S., Ando, M., Stella, M.C., and Comoglio, P.M. (1996). Ets up-regulates MET transcription. Oncogene 13, 1911-1917.
Gandino, L., Longati, P., Medico, E., Prat, M., and Comoglio, P.M. (1994). Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. J Biol Chem 269, 1815-1820.
Gherardi, E., Sharpe, M., Lane, K., Sirulnik, A., and Stoker, M. (1993). Hepatocyte growth factor/scatter factor (HGF/SF), the c-met receptor and the behaviour of epithelial cells. Symp Soc Exp Biol 47, 163-181.
Giordano, S., Corso, S., Conrotto, P., Artigiani, S., Gilestro, G., Barberis, D., Tamagnone, L., and Comoglio, P.M. (2002). The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4, 720-724.
Go, H., Jeon, Y.K., Park, H.J., Sung, S.W., Seo, J.W., and Chung, D.H. (2010). High MET gene copy number leads to shorter survival in patients with non-small cell lung cancer. J Thorac Oncol 5, 305-313.
Gual, P., Giordano, S., Williams, T.A., Rocchi, S., Van Obberghen, E., and Comoglio, P.M. (2000). Sustained recruitment of phospholipase C-gamma to Gab1 is required for HGF-induced branching tubulogenesis. Oncogene 19, 1509-1518.
Harvey, P., Warn, A., Newman, P., Perry, L.J., Ball, R.Y., and Warn, R.M. (1996). Immunoreactivity for hepatocyte growth factor/scatter factor and its receptor, met, in human lung carcinomas and malignant mesotheliomas. J Pathol 180, 389-394.
Herbst, R.S., Heymach, J.V., and Lippman, S.M. (2008). Lung cancer. N Engl J Med 359, 1367-1380.
Hiroumi, H., Dosaka-Akita, H., Yoshida, K., Shindoh, M., Ohbuchi, T., Fujinaga, K., and Nishimura, M. (2001). Expression of E1AF/PEA3, an Ets-related transcription factor in human non-small-cell lung cancers: its relevance in cell motility and invasion. Int J Cancer 93, 786-791.
Houldsworth, J., Cordon-Cardo, C., Ladanyi, M., Kelsen, D.P., and Chaganti, R.S. (1990). Gene amplification in gastric and esophageal adenocarcinomas. Cancer Res 50, 6417-6422.
Hsu, H., Xiong, J., and Goeddel, D.V. (1995). The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell 81, 495-504.
Huh, C.G., Factor, V.M., Sanchez, A., Uchida, K., Conner, E.A., and Thorgeirsson, S.S. (2004). Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proc Natl Acad Sci U S A 101, 4477-4482.
Ichimura, E., Maeshima, A., Nakajima, T., and Nakamura, T. (1996). Expression of c-met/HGF receptor in human non-small cell lung carcinomas in vitro and in vivo and its prognostic significance. Jpn J Cancer Res 87, 1063-1069.
Jeffers, M., Schmidt, L., Nakaigawa, N., Webb, C.P., Weirich, G., Kishida, T., Zbar, B., and Vande Woude, G.F. (1997a). Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci U S A 94, 11445-11450.
Jeffers, M., Taylor, G.A., Weidner, K.M., Omura, S., and Vande Woude, G.F. (1997b). Degradation of the Met tyrosine kinase receptor by the ubiquitin-proteasome pathway. Mol Cell Biol 17, 799-808.
Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., and Thun, M.J. (2009). Cancer statistics, 2009. CA Cancer J Clin 59, 225-249.
Jiang, Y., Xu, W., Lu, J., He, F., and Yang, X. (2001). Invasiveness of hepatocellular carcinoma cell lines: contribution of hepatocyte growth factor, c-met, and transcription factor Ets-1. Biochem Biophys Res Commun 286, 1123-1130.
Jo, M., Stolz, D.B., Esplen, J.E., Dorko, K., Michalopoulos, G.K., and Strom, S.C. (2000). Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem 275, 8806-8811.
Jun, H.T., Sun, J., Rex, K., Radinsky, R., Kendall, R., Coxon, A., and Burgess, T.L. (2007). AMG 102, a fully human anti-hepatocyte growth factor/scatter factor neutralizing antibody, enhances the efficacy of temozolomide or docetaxel in U-87 MG cells and xenografts. Clin Cancer Res 13, 6735-6742.
Kanteti, R., Nallasura, V., Loganathan, S., Tretiakova, M., Kroll, T., Krishnaswamy, S., Faoro, L., Cagle, P., Husain, A.N., Vokes, E.E., Lang, D., and Salgia, R. (2009). PAX5 is expressed in small-cell lung cancer and positively regulates c-Met transcription. Lab Invest 89, 301-314.
Kokoszynska, K., Krynski, J., Rychlewski, L., and Wyrwicz, L.S. (2009). Unexpected domain composition of MACC1 links MET signaling and apoptosis. Acta Biochim Pol 56, 317-323.
Kong-Beltran, M., Seshagiri, S., Zha, J., Zhu, W., Bhawe, K., Mendoza, N., Holcomb, T., Pujara, K., Stinson, J., Fu, L., Severin, C., Rangell, L., Schwall, R., Amler, L., Wickramasinghe, D., and Yauch, R. (2006). Somatic mutations lead to an oncogenic deletion of met in lung cancer. Cancer Res 66, 283-289.
Koochekpour, S., Jeffers, M., Rulong, S., Taylor, G., Klineberg, E., Hudson, E.A., Resau, J.H., and Vande Woude, G.F. (1997). Met and hepatocyte growth factor/scatter factor expression in human gliomas. Cancer Res 57, 5391-5398.
Krishnaswamy, S., Kanteti, R., Duke-Cohan, J.S., Loganathan, S., Liu, W., Ma, P.C., Sattler, M., Singleton, P.A., Ramnath, N., Innocenti, F., Nicolae, D.L., Ouyang, Z., Liang, J., Minna, J., Kozloff, M.F., Ferguson, M.K., Natarajan, V., Wang, Y.C., Garcia, J.G., Vokes, E.E., and Salgia, R. (2009). Ethnic differences and functional analysis of MET mutations in lung cancer. Clin Cancer Res 15, 5714-5723.
Kubo, T., Yamamoto, H., Lockwood, W.W., Valencia, I., Soh, J., Peyton, M., Jida, M., Otani, H., Fujii, T., Ouchida, M., Takigawa, N., Kiura, K., Shimizu, K., Date, H., Minna, J.D., Varella-Garcia, M., Lam, W.L., Gazdar, A.F., and Toyooka, S. (2009). MET gene amplification or EGFR mutation activate MET in lung cancers untreated with EGFR tyrosine kinase inhibitors. Int J Cancer 124, 1778-1784.
Liang, H., O'Reilly, S., Liu, Y., Abounader, R., Laterra, J., Maher, V.M., and McCormick, J.J. (2004). Sp1 regulates expression of MET, and ribozyme-induced down-regulation of MET in fibrosarcoma-derived human cells reduces or eliminates their tumorigenicity. Int J Oncol 24, 1057-1067.
Liu, Y. (1998). The human hepatocyte growth factor receptor gene: complete structural organization and promoter characterization. Gene 215, 159-169.
Ma, P.C., Jagadeeswaran, R., Jagadeesh, S., Tretiakova, M.S., Nallasura, V., Fox, E.A., Hansen, M., Schaefer, E., Naoki, K., Lader, A., Richards, W., Sugarbaker, D., Husain, A.N., Christensen, J.G., and Salgia, R. (2005). Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res 65, 1479-1488.
Ma, P.C., Maulik, G., Christensen, J., and Salgia, R. (2003). c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev 22, 309-325.
Ma, P.C., Tretiakova, M.S., MacKinnon, A.C., Ramnath, N., Johnson, C., Dietrich, S., Seiwert, T., Christensen, J.G., Jagadeeswaran, R., Krausz, T., Vokes, E.E., Husain, A.N., and Salgia, R. (2008). Expression and mutational analysis of MET in human solid cancers. Genes Chromosomes Cancer 47, 1025-1037.
Maroun, C.R., Holgado-Madruga, M., Royal, I., Naujokas, M.A., Fournier, T.M., Wong, A.J., and Park, M. (1999). The Gab1 PH domain is required for localization of Gab1 at sites of cell-cell contact and epithelial morphogenesis downstream from the met receptor tyrosine kinase. Mol Cell Biol 19, 1784-1799.
Mascarenhas, J.B., Littlejohn, E.L., Wolsky, R.J., Young, K.P., Nelson, M., Salgia, R., and Lang, D. (2010). PAX3 and SOX10 activate MET receptor expression in melanoma. Pigment Cell Melanoma Res 23, 225-237.
Masuya, D., Huang, C., Liu, D., Nakashima, T., Kameyama, K., Haba, R., Ueno, M., and Yokomise, H. (2004). The tumour-stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients. Br J Cancer 90, 1555-1562.
Matsuki, H., Yonezawa, K., Obata, K., Iwata, K., Nakamura, H., Okada, Y., and Seiki, M. (2003). Monoclonal antibodies with defined recognition sequences in the stem region of CD44: detection of differential glycosylation of CD44 between tumor and stromal cells in tissue. Cancer Res 63, 8278-8283.
Matsumoto, K., and Nakamura, T. (2003). NK4 (HGF-antagonist/angiogenesis inhibitor) in cancer biology and therapeutics. Cancer Sci 94, 321-327.
Michieli, P., Basilico, C., Pennacchietti, S., Maffe, A., Tamagnone, L., Giordano, S., Bardelli, A., and Comoglio, P.M. (1999). Mutant Met-mediated transformation is ligand-dependent and can be inhibited by HGF antagonists. Oncogene 18, 5221-5231.
Michieli, P., Mazzone, M., Basilico, C., Cavassa, S., Sottile, A., Naldini, L., and Comoglio, P.M. (2004). Targeting the tumor and its microenvironment by a dual-function decoy Met receptor. Cancer Cell 6, 61-73.
Morozov, V.M., Massoll, N.A., Vladimirova, O.V., Maul, G.G., and Ishov, A.M. (2008). Regulation of c-met expression by transcription repressor Daxx. Oncogene 27, 2177-2186.
Nakamura, Y., Niki, T., Goto, A., Morikawa, T., Miyazawa, K., Nakajima, J., and Fukayama, M. (2007). c-Met activation in lung adenocarcinoma tissues: an immunohistochemical analysis. Cancer Sci 98, 1006-1013.
Nakanishi, K., Fujimoto, J., Ueki, T., Kishimoto, K., Hashimoto-Tamaoki, T., Furuyama, J., Itoh, T., Sasaki, Y., and Okamoto, E. (1999). Hepatocyte growth factor promotes migration of human hepatocellular carcinoma via phosphatidylinositol 3-kinase. Clin Exp Metastasis 17, 507-514.
Naor, D., Sionov, R.V., and Ish-Shalom, D. (1997). CD44: structure, function, and association with the malignant process. Adv Cancer Res 71, 241-319.
Okuda, K., Sasaki, H., Yukiue, H., Yano, M., and Fujii, Y. (2008). Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci 99, 2280-2285.
Olivero, M., Rizzo, M., Madeddu, R., Casadio, C., Pennacchietti, S., Nicotra, M.R., Prat, M., Maggi, G., Arena, N., Natali, P.G., Comoglio, P.M., and Di Renzo, M.F. (1996). Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer 74, 1862-1868.
Onozato, R., Kosaka, T., Kuwano, H., Sekido, Y., Yatabe, Y., and Mitsudomi, T. (2009). Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain in primary resected lung cancers. J Thorac Oncol 4, 5-11.
Orian-Rousseau, V., Chen, L., Sleeman, J.P., Herrlich, P., and Ponta, H. (2002). CD44 is required for two consecutive steps in HGF/c-Met signaling. Genes Dev 16, 3074-3086.
Papotti, M., Olivero, M., Volante, M., Negro, F., Prat, M., Comoglio, P.M., and DiRenzo, M.F. (2000). Expression of Hepatocyte Growth Factor (HGF) and its Receptor (MET) in Medullary Carcinoma of the Thyroid. Endocr Pathol 11, 19-30.
Park, W.S., Dong, S.M., Kim, S.Y., Na, E.Y., Shin, M.S., Pi, J.H., Kim, B.J., Bae, J.H., Hong, Y.K., Lee, K.S., Lee, S.H., Yoo, N.J., Jang, J.J., Pack, S., Zhuang, Z., Schmidt, L., Zbar, B., and Lee, J.Y. (1999). Somatic mutations in the kinase domain of the Met/hepatocyte growth factor receptor gene in childhood hepatocellular carcinomas. Cancer Res 59, 307-310.
Paumelle, R., Tulasne, D., Kherrouche, Z., Plaza, S., Leroy, C., Reveneau, S., Vandenbunder, B., and Fafeur, V. (2002). Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. Oncogene 21, 2309-2319.
Pennacchietti, S., Michieli, P., Galluzzo, M., Mazzone, M., Giordano, S., and Comoglio, P.M. (2003). Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 3, 347-361.
Ponta, H., Wainwright, D., and Herrlich, P. (1998). The CD44 protein family. Int J Biochem Cell Biol 30, 299-305.
Ponzetto, C., Bardelli, A., Zhen, Z., Maina, F., dalla Zonca, P., Giordano, S., Graziani, A., Panayotou, G., and Comoglio, P.M. (1994). A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 77, 261-271.
Ponzetto, C., Giordano, S., Peverali, F., Della Valle, G., Abate, M.L., Vaula, G., and Comoglio, P.M. (1991). c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase. Oncogene 6, 553-559.
Puri, N., and Salgia, R. (2008). Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in non-small cell lung cancer. J Carcinog 7, 9.
Ramos-Nino, M.E., Blumen, S.R., Pass, H., and Mossman, B.T. (2007). Fra-1 governs cell migration via modulation of CD44 expression in human mesotheliomas. Mol Cancer 6, 81.
Reed, J.C., Doctor, K.S., and Godzik, A. (2004). The domains of apoptosis: a genomics perspective. Sci STKE 2004, 1-29.
Rodrigues, G.A., and Park, M. (1994). Autophosphorylation modulates the kinase activity and oncogenic potential of the Met receptor tyrosine kinase. Oncogene 9, 2019-2027.
Rong, S., Segal, S., Anver, M., Resau, J.H., and Vande Woude, G.F. (1994). Invasiveness and metastasis of NIH 3T3 cells induced by Met-hepatocyte growth factor/scatter factor autocrine stimulation. Proc Natl Acad Sci U S A 91, 4731-4735.
Rosario, M., and Birchmeier, W. (2003). How to make tubes: signaling by the Met receptor tyrosine kinase. Trends Cell Biol 13, 328-335.
Rosen, E.M., and Goldberg, I.D. (1997). Regulation of angiogenesis by scatter factor. EXS 79, 193-208.
Saeki, H., Oda, S., Kawaguchi, H., Ohno, S., Kuwano, H., Maehara, Y., and Sugimachi, K. (2002). Concurrent overexpression of Ets-1 and c-Met correlates with a phenotype of high cellular motility in human esophageal cancer. Int J Cancer 98, 8-13.
Schmidt, C., Bladt, F., Goedecke, S., Brinkmann, V., Zschiesche, W., Sharpe, M., Gherardi, E., and Birchmeier, C. (1995). Scatter factor/hepatocyte growth factor is essential for liver development. Nature 373, 699-702.
Schmidt, L., Duh, F.M., Chen, F., Kishida, T., Glenn, G., Choyke, P., Scherer, S.W., Zhuang, Z., Lubensky, I., Dean, M., Allikmets, R., Chidambaram, A., Bergerheim, U.R., Feltis, J.T., Casadevall, C., Zamarron, A., Bernues, M., Richard, S., Lips, C.J., Walther, M.M., Tsui, L.C., Geil, L., Orcutt, M.L., Stackhouse, T., Lipan, J., Slife, L., Brauch, H., Decker, J., Niehans, G., Hughson, M.D., Moch, H., Storkel, S., Lerman, M.I., Linehan, W.M., and Zbar, B. (1997). Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16, 68-73.
Seol, D.W., Chen, Q., Smith, M.L., and Zarnegar, R. (1999). Regulation of the c-met proto-oncogene promoter by p53. J Biol Chem 274, 3565-3572.
Seol, D.W., Chen, Q., and Zarnegar, R. (2000). Transcriptional activation of the hepatocyte growth factor receptor (c-met) gene by its ligand (hepatocyte growth factor) is mediated through AP-1. Oncogene 19, 1132-1137.
Seol, D.W., and Zarnegar, R. (1998). Structural and functional characterization of the mouse c-met proto-oncogene (hepatocyte growth factor receptor) promoter. Biochim Biophys Acta 1395, 252-258.
Seth, A., and Watson, D.K. (2005). ETS transcription factors and their emerging roles in human cancer. Eur J Cancer 41, 2462-2478.
Soman, N.R., Correa, P., Ruiz, B.A., and Wogan, G.N. (1991). The TPR-MET oncogenic rearrangement is present and expressed in human gastric carcinoma and precursor lesions. Proc Natl Acad Sci U S A 88, 4892-4896.
Spira, A., and Ettinger, D.S. (2004). Multidisciplinary management of lung cancer. N Engl J Med 350, 379-392.
Sprick, M.R., Weigand, M.A., Rieser, E., Rauch, C.T., Juo, P., Blenis, J., Krammer, P.H., and Walczak, H. (2000). FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2. Immunity 12, 599-609.
Stein, U., Dahlmann, M., and Walther, W. (2009a). MACC1 - more than metastasis? Facts and predictions about a novel gene. J Mol Med 88, 11-18.
Stein, U., Smith, J., Walther, W., and Arlt, F. (2009b). MACC1 controls Met: what a difference an Sp1 site makes. Cell Cycle 8, 2467-2469.
Stein, U., Walther, W., Arlt, F., Schwabe, H., Smith, J., Fichtner, I., Birchmeier, W., and Schlag, P.M. (2009c). MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nat Med 15, 59-67.
Stellrecht, C.M., and Gandhi, V. (2009). MET receptor tyrosine kinase as a therapeutic anticancer target. Cancer Lett 280, 1-14.
Takayama, H., LaRochelle, W.J., Sharp, R., Otsuka, T., Kriebel, P., Anver, M., Aaronson, S.A., and Merlino, G. (1997). Diverse tumorigenesis associated with aberrant development in mice overexpressing hepatocyte growth factor/scatter factor. Proc Natl Acad Sci U S A 94, 701-706.
Takeuchi, H., Bilchik, A., Saha, S., Turner, R., Wiese, D., Tanaka, M., Kuo, C., Wang, H.J., and Hoon, D.S. (2003). c-MET expression level in primary colon cancer: a predictor of tumor invasion and lymph node metastases. Clin Cancer Res 9, 1480-1488.
Tan, Y.H., Krishnaswamy, S., Nandi, S., Kanteti, R., Vora, S., Onel, K., Hasina, R., Lo, F.Y., El-Hashani, E., Cervantes, G., Robinson, M., Kales, S.C., Lipkowitz, S., Karrison, T., Sattler, M., Vokes, E.E., Wang, Y.C., and Salgia, R. (2010). CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases. PLoS One 5, e8972.
Tatsukawa, H., Fukaya, Y., Frampton, G., Martinez-Fuentes, A., Suzuki, K., Kuo, T.F., Nagatsuma, K., Shimokado, K., Okuno, M., Wu, J., Iismaa, S., Matsuura, T., Tsukamoto, H., Zern, M.A., Graham, R.M., and Kojima, S. (2009). Role of transglutaminase 2 in liver injury via cross-linking and silencing of transcription factor Sp1. Gastroenterology 136, 1783-1795 e1710.
Tong, C.Y., Hui, A.B., Yin, X.L., Pang, J.C., Zhu, X.L., Poon, W.S., and Ng, H.K. (2004). Detection of oncogene amplifications in medulloblastomas by comparative genomic hybridization and array-based comparative genomic hybridization. J Neurosurg 100, 187-193.
Trusolino, L., and Comoglio, P.M. (2002). Scatter-factor and semaphorin receptors: cell signalling for invasive growth. Nat Rev Cancer 2, 289-300.
Tsarfaty, I., Rong, S., Resau, J.H., Rulong, S., da Silva, P.P., and Vande Woude, G.F. (1994). The Met proto-oncogene mesenchymal to epithelial cell conversion. Science 263, 98-101.
Tsuda, M., Davis, I.J., Argani, P., Shukla, N., McGill, G.G., Nagai, M., Saito, T., Lae, M., Fisher, D.E., and Ladanyi, M. (2007). TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition. Cancer Res 67, 919-929.
Tuck, A.B., Park, M., Sterns, E.E., Boag, A., and Elliott, B.E. (1996). Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol 148, 225-232.
Uehara, Y., Minowa, O., Mori, C., Shiota, K., Kuno, J., Noda, T., and Kitamura, N. (1995). Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373, 702-705.
Verras, M., Lee, J., Xue, H., Li, T.H., Wang, Y., and Sun, Z. (2007). The androgen receptor negatively regulates the expression of c-Met: implications for a novel mechanism of prostate cancer progression. Cancer Res 67, 967-975.
Wang, X., DeFrances, M.C., Dai, Y., Pediaditakis, P., Johnson, C., Bell, A., Michalopoulos, G.K., and Zarnegar, R. (2002). A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Mol Cell 9, 411-421.
Wierstra, I. (2008). Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes. Biochem Biophys Res Commun 372, 1-13.
Williams, B.A., Sugimura, H., Endo, C., Nichols, F.C., Cassivi, S.D., Allen, M.S., Pairolero, P.C., Deschamps, C., and Yang, P. (2006). Predicting postrecurrence survival among completely resected nonsmall-cell lung cancer patients. Ann Thorac Surg 81, 1021-1027.
Xiao, G.H., Jeffers, M., Bellacosa, A., Mitsuuchi, Y., Vande Woude, G.F., and Testa, J.R. (2001). Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci U S A 98, 247-252.
Yano, S., Wang, W., Li, Q., Matsumoto, K., Sakurama, H., Nakamura, T., Ogino, H., Kakiuchi, S., Hanibuchi, M., Nishioka, Y., Uehara, H., Mitsudomi, T., Yatabe, Y., and Sone, S. (2008). Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res 68, 9479-9487.
Zachow, R., and Uzumcu, M. (2007). The hepatocyte growth factor system as a regulator of female and male gonadal function. J Endocrinol 195, 359-371.
Zeng, Q., Chen, S., You, Z., Yang, F., Carey, T.E., Saims, D., and Wang, C.Y. (2002). Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B. J Biol Chem 277, 25203-25208.
Zhang, X., and Liu, Y. (2003). Suppression of HGF receptor gene expression by oxidative stress is mediated through the interplay between Sp1 and Egr-1. Am J Physiol Renal Physiol 284, F1216-1225.
Zhang, X., Yang, J., Li, Y., and Liu, Y. (2005). Both Sp1 and Smad participate in mediating TGF-beta1-induced HGF receptor expression in renal epithelial cells. Am J Physiol Renal Physiol 288, F16-26.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2013-08-12起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2014-08-12起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw