請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20378
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 蔡丰喬(Feng-Chiao Tsai) | |
dc.contributor.author | Si Cheok Kei | en |
dc.contributor.author | 施卓琪 | zh_TW |
dc.date.accessioned | 2021-06-08T02:46:47Z | - |
dc.date.copyright | 2017-08-23 | |
dc.date.issued | 2017 | |
dc.date.submitted | 2017-08-21 | |
dc.identifier.citation | '<Characterization of HPV and host genome interactions in primary head and neck cancers..pdf>.'
Chaffer, C. L., J. P. Brennan, J. L. Slavin, T. Blick, E. W. Thompson and E. D. Williams (2006). 'Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2.' Cancer Res 66(23): 11271-11278. Chang, J., S. Wang, Z. Zhang, X. Liu, Z. Wu, R. Geng, X. Ge, C. Dai, R. Liu, Q. Zhang, W. Li and J. Li (2015). 'Multiple receptor tyrosine kinase activation attenuates therapeutic efficacy of the fibroblast growth factor receptor 2 inhibitor AZD4547 in FGFR2 amplified gastric cancer.' Oncotarget 6(4): 2009-2022. Daniele, G., J. Corral, L. R. Molife and J. S. de Bono (2012). 'FGF receptor inhibitors: role in cancer therapy.' Curr Oncol Rep 14(2): 111-119. Del Piccolo, N., S. Sarabipour and K. Hristova (2017). 'A New Method to Study Heterodimerization of Membrane Proteins and Its Application to Fibroblast Growth Factor Receptors.' J Biol Chem 292(4): 1288-1301. Guo, M., W. Liu, S. Serra, S. L. Asa and S. Ezzat (2012). 'FGFR2 isoforms support epithelial-stromal interactions in thyroid cancer progression.' Cancer Res 72(8): 2017-2027. Johannessen, C. M., J. S. Boehm, S. Y. Kim, S. R. Thomas, L. Wardwell, L. A. Johnson, C. M. Emery, N. Stransky, A. P. Cogdill, J. Barretina, G. Caponigro, H. Hieronymus, R. R. Murray, K. Salehi-Ashtiani, D. E. Hill, M. Vidal, J. J. Zhao, X. Yang, O. Alkan, S. Kim, J. L. Harris, C. J. Wilson, V. E. Myer, P. M. Finan, D. E. Root, T. M. Roberts, T. Golub, K. T. Flaherty, R. Dummer, B. L. Weber, W. R. Sellers, R. Schlegel, J. A. Wargo, W. C. Hahn and L. A. Garraway (2010). 'COT drives resistance to RAF inhibition through MAP kinase pathway reactivation.' Nature 468(7326): 968-972. Katoh, M. (2016). 'Therapeutics Targeting FGF Signaling Network in Human Diseases.' Trends Pharmacol Sci 37(12): 1081-1096. Kelleher, F. C., H. O'Sullivan, E. Smyth, R. McDermott and A. Viterbo (2013). 'Fibroblast growth factor receptors, developmental corruption and malignant disease.' Carcinogenesis 34(10): 2198-2205. Magnusson, P. U., A. Dimberg, S. Mellberg, A. Lukinius and L. Claesson-Welsh (2007). 'FGFR-1 regulates angiogenesis through cytokines interleukin-4 and pleiotrophin.' Blood 110(13): 4214-4222. Nomura, S., H. Yoshitomi, S. Takano, T. Shida, S. Kobayashi, M. Ohtsuka, F. Kimura, H. Shimizu, H. Yoshidome, A. Kato and M. Miyazaki (2008). 'FGF10/FGFR2 signal induces cell migration and invasion in pancreatic cancer.' Br J Cancer 99(2): 305-313. O'Rorke, M. A., M. V. Ellison, L. J. Murray, M. Moran, J. James and L. A. Anderson (2012). 'Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis.' Oral Oncol 48(12): 1191-1201. Ornitz, D. M. and N. Itoh (2015). 'The Fibroblast Growth Factor signaling pathway.' Wiley Interdiscip Rev Dev Biol 4(3): 215-266. Parfenov, M., C. S. Pedamallu, N. Gehlenborg, S. S. Freeman, L. Danilova, C. A. Bristow, S. Lee, A. G. Hadjipanayis, E. V. Ivanova, M. D. Wilkerson, A. Protopopov, L. Yang, S. Seth, X. Song, J. Tang, X. Ren, J. Zhang, A. Pantazi, N. Santoso, A. W. Xu, H. Mahadeshwar, D. A. Wheeler, R. I. Haddad, J. Jung, A. I. Ojesina, N. Issaeva, W. G. Yarbrough, D. N. Hayes, J. R. Grandis, A. K. El-Naggar, M. Meyerson, P. J. Park, L. Chin, J. G. Seidman, P. S. Hammerman, R. Kucherlapati and N. Cancer Genome Atlas (2014). 'Characterization of HPV and host genome interactions in primary head and neck cancers.' Proc Natl Acad Sci U S A 111(43): 15544-15549. Schmitt-Ney, M. and J. F. Habener (2004). 'Cell-density-dependent regulation of actin gene expression due to changes in actin treadmilling.' Exp Cell Res 295(1): 236-244. Schultz, V., M. Suflita, X. Liu, X. Zhang, Y. Yu, L. Li, D. E. Green, Y. Xu, F. Zhang, P. L. DeAngelis, J. Liu and R. J. Linhardt (2017). 'Heparan Sulfate Domains Required for Fibroblast Growth Factor 1 and 2 Signaling through Fibroblast Growth Factor Receptor 1c.' J Biol Chem 292(6): 2495-2509. Shirakihara, T., K. Horiguchi, K. Miyazawa, S. Ehata, T. Shibata, I. Morita, K. Miyazono and M. Saitoh (2011). 'TGF-beta regulates isoform switching of FGF receptors and epithelial-mesenchymal transition.' EMBO J 30(4): 783-795. Tiong, K. H., L. Y. Mah and C.-O. Leong (2013). 'Functional roles of fibroblast growth factor receptors (FGFRs) signaling in human cancers.' Apoptosis 18(12): 1447-1468. Tomlinson, D. C., E. W. Baxter, P. M. Loadman, M. A. Hull and M. A. Knowles (2012). 'FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCgamma/COX-2-mediated mechanisms.' PLoS One 7(6): e38972. Touat, M., E. Ileana, S. Postel-Vinay, F. Andre and J. C. Soria (2015). 'Targeting FGFR Signaling in Cancer.' Clin Cancer Res 21(12): 2684-2694. Ueno, N., A. Shimizu, M. Kanai, Y. Iwaya, S. Ueda, J. Nakayama and M. K. Seo (2016). 'Enhanced Expression of Fibroblast Growth Factor Receptor 3 IIIc Promotes Human Esophageal Carcinoma Cell Proliferation.' J Histochem Cytochem 64(1): 7-17. Warnakulasuriya, S. (2009). 'Global epidemiology of oral and oropharyngeal cancer.' Oral Oncol 45(4-5): 309-316. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20378 | - |
dc.description.abstract | 頭頸部鱗狀上皮細胞癌(Head and neck squamous cell carcinoma , HNSCC)在台灣有較高的發病率和致死率,但目前對於HNSCC的治療方法並沒有太大的突破。HNSCC屬於容易轉移及復發的癌症,病患預後亦和轉移的出現有高度的相關;因此對於HNSCC的治療來說,如何有效阻止腫瘤轉移或許可以成為治療的關鍵。
因此我們嘗試去找出會影響頭頸癌移動的目標。由於先前有研究顯示FGFR (Fibroblast growth factor receptor)的突變﹑表現量增加等異常與乳癌﹑肺癌﹑多發性黑色素瘤等癌症的形成相關;而FGFR本身的功能亦涉及Epithelial–mesenchymal transition﹑血管新生等細胞移動的調控。那麼FGFR會否也有作用在頭頸癌的轉移中,能否有潛力作為治療頭頸癌的目標?為了回答這個問題,我們參考實驗室先前所做的一個針對FGFR的Screening結果中發現,FGFR2似乎可以抑制HNSCC細胞的移動,於是我們挑選FGFR2作為研究的目標。 我們分析了53位頭頸癌病人的腫瘤和正常組織中的FGFR2表現量,結果發現隨着臨床分期增加,FGFR2的總量有着下降的趨勢。為了知道FGFR2對細胞遷移的影響,我們進一步透過knockdown、overexpression等方法,改變細胞中FGFR2的表現量來研究FGFR2的功能。我們發現在FGFR2 knockdown後,頭頸癌細胞的移動速度會有明顯下降,細胞運動的方向性以及細胞間的協調性亦會變差。表示FGFR2在頭頸癌的遷移中可能有着促進的的角色。而分別overexpression FGFR2IIIb和IIIc後,細胞的移動也有輕微的下降,這個結果暗示著FGFR2可能需要FGFR2IIIb和FGFR2IIIc同時存在才能增加細胞的遷移速度。根據我們目前的研究結果,顯示FGFR2有可能影響頭頸癌細胞轉移,然而FGFR2調控頭頸癌細胞遷移的機轉仍需要更進一步的研究與探討才能釐清。 | zh_TW |
dc.description.abstract | Head and neck squamous cell carcinoma (HNSCC) has high metastasis and recurrent rates and causes high cancer-related mortality in Taiwan. However, there is still no effective treatment for HNSCC. We therefore aimed to identify novel therapeutic targets to prevent HNSCC metastasis.
Mutations and amplification of FGFR (Fibroblast growth factor receptor) genes were reported to be important in cell proliferation, differentiation and migration of many cancers, including breast cancer, lung cancer and melanoma. FGFRs were also reported to be associated with epithelial–mesenchymal transition, angiogenesis and regulation of cell migration. Therefore, our question is: Does FGFR participate in HNSCC metastasis? Could it be a potential targret in curing HNSCC? To answer this question, we used shRNAs targeting FGFRs to systemically examine the effect of FGFR on HNSCC cell migration. The screen result revealed that FGFR2 knockdown significantly reduced HNSCC motility. Therefore, we proposed that FGFR2 may promote HNSCC cell migration. To validate our hypothesis, we examined the expression level of FGFR2 in 53 tumor samples from HNSCC patients of various stages. We found that FGFR2 expression was decreased in late-stage HNSCC. To further understand the role of FGFR2 in cancer cell migration, we knocked-down, overexpressed and rescued FGFR2 levels in SAS cells, and measured how such treatments affected HNSCC cell migration. We found that FGFR2 knockdown significant decreased cell migration, probably through impairing directionality and cell-cell coordination. These results implied that FGFR2 might promote HNSCC cell migration. Interesingly, FGFR2IIIb or IIIc overexpression slightly decreased cell migration. These results suggested that there might be some interaction between FGFR2IIIb and FGFR2IIIc. Based on our findings, FGFR2 may play an important role in HNSCC metastasis. Further investigations are currently under the way to clarify the mechanism how FGFR2 changes HNSCC migration. | en |
dc.description.provenance | Made available in DSpace on 2021-06-08T02:46:47Z (GMT). No. of bitstreams: 1 ntu-106-R04443004-1.pdf: 8604626 bytes, checksum: 4852f5e042b585a445b44488201c990c (MD5) Previous issue date: 2017 | en |
dc.description.tableofcontents | 1 導論 1
1.1 頭頸部鱗狀上皮細胞癌(HEAD AND NECK SQUAMOUS CELL CARCINOMA , HNSCC) 1 1.1.1 頭頸癌概論 1 1.1.2 HNSCC目前的治療與限制 1 1.1.3 透過Screening找出有潛力的目標:FGFR2 2 1.2 FGFR的結構及功能 5 1.3 研究目標 7 2 材料與方法 8 2.1 細胞培養 8 2.2 CELL MIGRATION ASSAY (細胞遷移實驗) 8 2.2.1 前置作業 8 2.2.2 Live cell imaging (活細胞攝影) 8 2.3 WESTERN BLOT (西方墨點法) 9 2.3.1 細胞蛋白質萃取及定量 9 2.3.2 做膠及電泳 10 2.3.3 抗體免疫結合 10 2.3.4 Western blot buffer 成份配方 11 2.4 QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION(QPCR) 即時聚合酶鏈鎖反應 12 2.4.1 細胞RNA萃取 12 2.4.2 反轉錄成cDNA 12 2.4.3 即時聚合酶連鎖反應(Real-time PCR) 12 2.5 TRANSFECTION 13 2.6 VIRAL INFECTION 14 3 結果 16 3.1 FGFR2在頭頸癌細胞株的表現 16 3.2 抑制FGFR會抑制頭頸癌細胞的遷移 20 3.2.1 製作FGFR2 knockdown的shRNA lentivirus(慢病毒) 22 3.2.2 FGFR2被knockdown後,細胞的遷移能力會下降 23 3.2.3 製作能夠專一作用在FGFR2IIIb 和FGFR2IIIc的shRNA 25 3.2.4 透過QPCR定量FGFR2IIIb和FGFR2IIIc的knockdown效果 26 3.2.5 FGFR2IIIb的knockdown可令細胞遷移能力下降,IIIb和IIIc都被knockdown能進一步抑制細胞遷移能力 29 3.2.6 小結 31 3.3 透過OVEREXPRESSION(過度表現)FGFR2來探討FGFR2對細胞遷移的影響 32 3.3.1 製作pEYFP-P2A-FGFR2IIIb/IIIc的質體 32 3.3.2 Overexpression FGFR2對細胞遷移沒有影響 35 3.3.3 重新表現FGFR2IIIb無法令細胞的遷移回復正常 38 3.3.4 用Site-Directed Mutagenesis修正購入的FGFR2質體上的突變 40 3.3.5 小結 43 3.4 探討FGFR2 KNOCKDOWN會抑制細胞遷移的原因 44 4 討論 48 4.1 FGFR2在頭頸癌細胞隨臨床分期改變 48 4.2 FGFR2IIIB和IIIC都有促進細胞遷移 49 4.3 OVEREXPRESSION FGFR2 49 4.4 FGFR2所調控的訊息路徑 51 5 參考資料 52 6 補充資料 55 | |
dc.language.iso | zh-TW | |
dc.title | 纖維母細胞生長因子受器第二型在頭頸部鱗狀上皮細胞癌中對細胞遷移的影響 | zh_TW |
dc.title | FGFR2 in head and neck squamous cell carcinoma (HNSCC):focusing on cancer cell migration | en |
dc.type | Thesis | |
dc.date.schoolyear | 105-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 賈景山(Jean-San Chia),張玉芳(Julia Yu-Fong Chang) | |
dc.subject.keyword | 頭頸癌,FGFR2,細胞遷移,癌症轉移,Splice variant, | zh_TW |
dc.subject.keyword | Head and neck squamous cell carcinoma (HNSCC),Fibroblast growth factor receptor 2 (FGFR2),cell migration,cancer metastasis,Splice variant, | en |
dc.relation.page | 69 | |
dc.identifier.doi | 10.6342/NTU201704087 | |
dc.rights.note | 未授權 | |
dc.date.accepted | 2017-08-21 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥理學研究所 | zh_TW |
顯示於系所單位: | 藥理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-106-1.pdf 目前未授權公開取用 | 8.4 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。