進階搜尋


   電子論文尚未授權公開,紙本請查館藏目錄
(※如查詢不到或館藏狀況顯示「閉架不公開」,表示該本論文不在書庫,無法取用。)
系統識別號 U0026-1908201513493600
論文名稱(中文) 探討Stat3在癌細胞中轉錄調控NRP1的表現
論文名稱(英文) Stat3 transcriptionally regulates NRP1 expression in cancer cells
校院名稱 成功大學
系所名稱(中) 口腔醫學研究所
系所名稱(英) Institute of Oral Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 歐盈佛
研究生(英文) Ying-Fo Ou
學號 T46024015
學位類別 碩士
語文別 中文
論文頁數 78頁
口試委員 指導教授-陳玉玲
召集委員-洪澤民
口試委員-洪建中
口試委員-劉柯俊
中文關鍵字 訊息傳遞轉錄活化基因3  神經纖毛蛋白質-1 
英文關鍵字 Signal transducers and activator of transcription 3 (Stat3)  Neuropilin-1 (NRP1) 
學科別分類
中文摘要 肺癌在本國屬於死亡率第一的癌症,而口腔癌近年來在本國是增加趨勢最快的癌症,因此兩者的致癌機轉及惡化關鍵都是我們想深入探討的課題。訊息傳遞轉錄活化基因3 (Signal transducers and activator of transcription 3 ; Stat3) 已知在多種癌細胞和腫瘤微環境中都呈現持續活化的現象,被認為是致癌性轉錄因子,在過去的研究被證實,可能會影響腫瘤細胞的增生和轉移。神經纖毛蛋白質-1 (Neuropilin-1 ; NRP1)已知是可結合多種生長因子的穿膜蛋白,傳遞相關活化訊息,並且在較惡性及高轉移性的腫瘤中會有較高量表現。在先前的研究發現標靶NRP1可以促進腫瘤血管通透性、並增加藥物穿透癌組織,而有較好的癌症治療效果。
我們先前的研究已篩選出可標靶NRP1的胜肽DG2,具專一性及高親合性標靶NRP1,此外我們也發現在高轉移的肺癌細胞及較惡性的口腔癌細胞中,NRP1及活化的Stat3均有較高表現且表現量有正相關,並且利用線上軟體預測出NRP1啟動子上可能具有Stat3的結合位。 因此本研究計畫欲探討Stat3與NRP1之間互相調控的關係,並研究標靶NRP1/Stat3途徑對於轉移性癌細胞的影響為何。在此我們使用染色體免疫共沈澱和啟動子檢測法證實Stat3會結合到NRP1啟動子上,進而調控NRP1的表現。進而也利用免疫螢光法及流式細胞儀觀察到標靶NRP1的胜肽DG2對於高轉移的肺癌細胞及較惡性的口腔癌細胞有較高的親合性。我們也在活體實驗上看到外部修飾DG2的內包螢光PLGA奈米球會駐留在腫瘤處。藉由目前的實驗成果,我們將在未來的實驗中探討DG2攜帶Stat3抑制劑是否可達到有效抑制高轉移及較惡性的腫瘤形成。希望本研究成果在未來能為高轉移性及較惡性腫瘤提供新的治療標靶及策略。
英文摘要 In our previous studies, we have identified a NRP1-targeting peptide, DG2, could specifically bind to NRP1. We also found that the expression of activated Stat3 and NRP1 has positively correlation in highly metastatic lung cancer cells and malignant oral cancer cells. In addition, we found the promoter region of NRP1 has a potential Stat3 binding site and may be regulated by Stat3. Therefore, in this study, we want to explore the relationship between Stat3 and NRP1 regulation, and examine the anticancer effects of targeting Stat3/NRP1 pathway on metastatic cancer cells. Here, we confirmed that Stat3 binds to promoter of NRP1 and transcriptional activates the expression of NRP1. Also we found DG2 can preferentially bind to metastatic lung cancer cells and malignant oral cancer cells. In vivo study also showed the PLGA nanoparticles that modified with DG2 at external part would reside in the tumor after systematic administration. With the present experimental results, it will be important to evaluate whether DG2-delivered Stat3 inhibitors can effectively suppress metastatic and malignant cancer formation in vivo in the future study. Hoping the findings of this study may provide a new therapeutic target and useful strategies for the treatment of malignant cancer in the future.

Key words: Signal transducers and activator of transcription 3 (Stat3), Neuropilin-1 (NRP1)
論文目次 中文摘要 I
英文延伸摘要 III
致謝 VII
目錄 IX
英文縮寫檢索表 XIII
緒論 1
一、肺癌(Lung cancer) 1
二、口腔癌(Oral cancer) 3
三、癌轉移(Cancer metastasis) 4
四、訊息傳遞轉錄活化基因3
(Signal transducers and activator of transcription 3;Stat3 ) 5
五、訊息傳遞轉錄活化基因3與腫瘤(Stat3 in cancer) 7
六、神經纖毛蛋白質-1(Neuropilin-1) 8
七、神經纖毛蛋白質-1與腫瘤(Neuropilin-1 in cancer) 9
研究動機 10
材料與方法 12
一、 細胞培養(Cell culture) 12
1-1 細胞簡介 12
1-2 細胞解凍 12
1-3細胞冷凍保存 13
1-4 繼代培養細胞 14
1-5 細胞計數 14
二、細胞蛋白質表現分析(Protein expression assay) 15
2-1 細胞蛋白質樣品收集 15
2-2 蛋白質定量 16
2-3 西方點墨法 16
2-3-1 蛋白質之樣品製備 16
2-3-2 SDS-聚丙烯胺膠體電泳(SDS-polyacrylamide gel electrophoresis) 17
2-3-3 轉印(Electrotransfer) 19
2-3-4 免疫轉漬法(Immunobloting) 20
三、 細胞內RNA表現分析(mRNA expression assay) 21
3-1 細胞內RNA萃取 21
3-2 RNA及DNA定量 21
3-3反轉錄酶反應(Reverse transcription) 22
3-4聚合錄酶連鎖反應(polymerase chain reaction, PCR) 23
3-5洋菜膠體電泳分析(Agarose gel electrophoresis) 24
3-6即時定量PCR(qRT-PCR) 25
四、轉染(Transfection) 26
五、病毒感染(virus infection) 27
六、螢光素酶報導測定(Luciferase reporter assay) 28
七、染色質免疫沈澱技術
(Chromatin immunoprecipitation assay, ChIP) 29

八、細胞行為分析系統
(Electric Cell-Substrate Impedance Sensing, ECIS) 31
九、細胞螢光染色(Immunofluorescence) 31
十、流式細胞儀(Flow cytometry) 32
十一、腫瘤偵測的小鼠模式(Tumor detection in mice model) 33
十二、統計分析 34
十三、材料 34
十四、儀器 36

實驗結果 37
一、訊息傳遞轉錄活化基因(Signal transducers and activator of transcription 3 ; Stat3)與神經纖毛蛋白質-1(Neuropilin-1 ; NRP1)在高轉移性、較惡性的肺癌細胞及口腔癌細胞中會有較高的表現 37
二、在肺癌細胞及口腔癌細胞中Stat3的表現量正向調控NRP1表現量 38
三、NRP1啟動子(promoter)上具有Stat3結合位(DNA binding site) 39
四、Stat3藉由結合到NRP1啟動子(promoter)調控NRP1的表現 40
五、DG2對高轉移的肺癌細胞及口腔癌細胞有較高的親合性 41
六、在高轉移性癌細胞中DG2抑制Stat3與NRP1的表現 42
七、在動物實驗中DG2會滯留在腫瘤處的時間較長 43
討論 44
結論 51
參考文獻 52
圖目錄 62
圖一、口腔癌細胞OECM-1與SAS的移行能力分析 62
圖二、Stat3與NRP1在不同高轉移性癌細胞中的表現 63
圖三、Stat3與NRP1在不同高轉移性癌細胞中的表現 64
圖四、Stat3與NRP1在不同抗藥性癌細胞中的表現 65
圖五、在肺癌及口腔癌細胞中Stat3的活化與NRP1的表現呈正相關 66
圖五、在肺癌及口腔癌細胞中Stat3的活化與NRP1的表現呈正相關 67
圖六、NRP1的啟動子上具有Stat3的結合位 68
圖七、Stat3影響NRP1的啟動子活性 69
圖八、染色質免疫沈澱技術(Chromatin immunoprecipitation assay, ChIP)證實Stat3會結合到NRP1的啟動子上 70
圖九、DG2與高轉移的肺癌細胞及口腔癌細胞有較高的親合性 71
圖十、DG2在高轉移的肺癌細胞及口腔癌細胞有較強的結合性 72
圖十一、DG2在不同高轉移性癌細胞中對Stat3與NRP1的影響 73
圖十二、動物實驗中DG2會滯留在腫瘤處 74
附圖目錄 75
附圖一、Stat3與NRP1在不同口腔癌細胞中的表現 75
附圖二、肺癌細胞中IL-6對於Stat3的活化及NRP1表現的影響 76
附圖三、動物實驗中抑制Stat3或NRP1會影響腫瘤生成大小 77
附表目錄 78
附表一、線上軟體預測NRP1啟動子上Stat3的結合位 78
參考文獻 Acharya, S., and Sahoo, S.K. (2011). PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Advanced drug delivery reviews 63, 170-183.

Barr, M., Byrne, A., Duffy, A., Condron, C., Devocelle, M., Harriott, P., Bouchier-Hayes, D., and Harmey, J. (2005). A peptide corresponding to the neuropilin-1-binding site on VEGF165 induces apoptosis of neuropilin-1-expressing breast tumour cells. British journal of cancer 92, 328-333.

Becker, S., Groner, B., and Müller, C.W. (1998). Three-dimensional structure of the Stat3β homodimer bound to DNA. Nature 394, 145-151.

Benekli, M., Baer, M.R., Baumann, H., and Wetzler, M. (2003). Signal transducer and activator of transcription proteins in leukemias. Blood 101, 2940-2954.

Block, K.M., Hanke, N.T., Maine, E.A., and Baker, A.F. (2012). IL-6 stimulates STAT3 and Pim-1 kinase in pancreatic cancer cell lines. Pancreas 41, 773.

Brambilla, E., Constantin, B., Drabkin, H., and Roche, J. (2000). Semaphorin SEMA3F localization in malignant human lung and cell lines: A suggested role in cell adhesion and cell migration. The American journal of pathology 156, 939-950.

Bromberg, J. (2002). Stat proteins and oncogenesis. The Journal of clinical investigation 109, 1139-1142.

Bromberg, J., and Darnell Jr, J.E. (2000). The role of STATs in transcriptional control and their impact on cellular function. Oncogene 19, 2468-2473.

Cao, Y., Guangqi, E., Wang, E., Pal, K., Dutta, S.K., Bar-Sagi, D., and Mukhopadhyay, D. (2012). VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res 72, 3912-3918.


Chaffer, C.L., and Weinberg, R.A. (2011). A perspective on cancer cell metastasis. Science 331, 1559-1564.

Chang, Q., Bournazou, E., Sansone, P., Berishaj, M., Gao, S.P., Daly, L., Wels, J., Theilen, T., Granitto, S., Zhang, X., et al. (2013). The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia (New York, NY) 15, 848-862.

Chang, T.-H., Tsai, M.-F., Su, K.-Y., Wu, S.-G., Huang, C.-P., Yu, S.-L., Yu, Y.-L., Lan, C.-C., Yang, C.-H., and Lin, S.-B. (2011). Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor. American journal of respiratory and critical care medicine 183, 1071-1079.

Chen, Y.J., Chang, J.T., Liao, C.T., Wang, H.M., Yen, T.C., Chiu, C.C., Lu, Y.C., Li, H.F., and Cheng, A.J. (2008). Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis. Cancer science 99, 1507-1514.

Chiou, S.H., Yu, C.C., Huang, C.Y., Lin, S.C., Liu, C.J., Tsai, T.H., Chou, S.H., Chien, C.S., Ku, H.H., and Lo, J.F. (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 14, 4085-4095.

Chu, Y.-W., Yang, P.-C., Yang, S.-C., Shyu, Y.-C., Hendrix, M.J., Wu, R., and Wu, C.-W. (1997). Selection of invasive and metastatic subpopulations from a human lung adenocarcinoma cell line. American journal of respiratory cell and molecular biology 17, 353-360.

da Cunha Santos, G., Shepherd, F.A., and Tsao, M.S. (2011). EGFR mutations and lung cancer. Annual review of pathology 6, 49-69.

Decker, T., Stockinger, S., Karaghiosoff, M., Müller, M., and Kovarik, P. (2002). IFNs and STATs in innate immunity to microorganisms. The Journal of clinical investigation 109, 1271-1277.

Duncan, S.A., Zhong, Z., Wen, Z., and Darnell, J.E. (1997). STAT signaling is active during early mammalian development. Developmental dynamics 208, 190-198.


Ellis, L.M. (2006). The role of neuropilins in cancer. Molecular cancer therapeutics 5, 1099-1107.

Fajersztajn, L., Veras, M., Barrozo, L.V., and Saldiva, P. (2013). Air pollution: a potentially modifiable risk factor for lung cancer. Nature reviews Cancer 13, 674-678.

Fang, Q.G., Shi, S., Li, Z.N., Zhang, X., Liua, F.Y., Xu, Z.F., and Sun, C.F. (2013). Squamous cell carcinoma of the buccal mucosa: Analysis of clinical presentation, outcome and prognostic factors. Molecular and clinical oncology 1, 531-534.

Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D., and Bray, F. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer Journal international du cancer 136, E359-386.

Fernandes, A., Hamburger, A.W., and Gerwin, B.I. (1999). ErbB‐2 kinase is required for constitutive stat 3 activation in malignant human lung epithelial cells. International journal of cancer 83, 564-570.

Feurino, L.W., Zhang, Y., Bharadwaj, U., Zhang, R., Li, F., Fisher, W.E., Brunicardi, F.C., Chen, C., Yao, Q., and Min, L. (2007). IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells. Cancer biology & therapy 6, 1096-1100.

Gabrielson, E. (2006). Worldwide trends in lung cancer pathology. Respirology 11, 533-538.

Garcia, R., Bowman, T.L., Niu, G., Yu, H., Minton, S., Muro-Cacho, C.A., Cox, C.E., Falcone, R., Fairclough, R., and Parsons, S. (2001). Constitutive activation of Stat3 by the Src and JAK tyrosine kinases participates in growth regulation of human breast carcinoma cells. Oncogene 20, 2499-2513.

Glaser, R., Zhang, H.Y., Yao, K.T., Zhu, H.C., Wang, F.X., Li, G.Y., Wen, D.S., and Li, Y.P. (1989). Two epithelial tumor cell lines (HNE-1 and HONE-1) latently infected with Epstein-Barr virus that were derived from nasopharyngeal carcinomas. Proceedings of the National Academy of Sciences of the United States of America 86, 9524-9528.

Grandis, J.R., Drenning, S.D., Zeng, Q., Watkins, S.C., Melhem, M.F., Endo, S., Johnson, D.E., Huang, L., He, Y., and Kim, J.D. (2000). Constitutive activation of Stat3 signaling abrogates apoptosis in squamous cell carcinogenesis in vivo. Proceedings of the National Academy of Sciences 97, 4227-4232.

Gridelli, C., Rossi, A., Carbone, D.P., Guarize, J., Karachaliou, N., Mok, T., Petrella, F., Spaggiari, L., and Rosell, R. (2015). Non-small-cell lung cancer. Nature Reviews Disease Primers.

Gu, C., Limberg, B.J., Whitaker, G.B., Perman, B., Leahy, D.J., Rosenbaum, J.S., Ginty, D.D., and Kolodkin, A.L. (2002). Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. Journal of Biological Chemistry 277, 18069-18076.

Hackshaw, A.K., Law, M.R., and Wald, N.J. (1997). The accumulated evidence on lung cancer and environmental tobacco smoke. Bmj 315, 980-988.

Hansel, D.E., Wilentz, R.E., Yeo, C.J., Schulick, R.D., Montgomery, E., and Maitra, A. (2004). Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. The American journal of surgical pathology 28, 347-356.

He, Q.Y., Chen, J., Kung, H.F., Yuen, A.P., and Chiu, J.F. (2004). Identification of tumor-associated proteins in oral tongue squamous cell carcinoma by proteomics. Proteomics 4, 271-278.

He, Z., and Tessier-Lavigne, M. (1997). Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 90, 739-751.

Hecht, S.S. (1999). Tobacco smoke carcinogens and lung cancer. J Natl Cancer I 91, 1194-1210.

Hong, T.M., Chen, Y.L., Wu, Y.Y., Yuan, A., Chao, Y.C., Chung, Y.C., Wu, M.H., Yang, S.C., Pan, S.H., Shih, J.Y., et al. (2007). Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 13, 4759-4768.


Ihle, J.N. (1996). STATs: signal transducers and activators of transcription. Cell 84, 331-334.

Ikuta, K., Takemura, K., Kihara, M., Nishimura, M., Ueda, N., Naito, S., Lee, E., Shimizu, E., and Yamauchi, A. (2005). Overexpression of constitutive signal transducer and activator of transcription 3 mRNA in cisplatin-resistant human non-small cell lung cancer cells. Oncology reports 13, 217-222.

Jänne, P.A., Shaw, A.T., Pereira, J.R., Jeannin, G., Vansteenkiste, J., Barrios, C., Franke, F.A., Grinsted, L., Zazulina, V., Smith, P., et al. (2013). Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. The Lancet Oncology 14, 38-47.

Jiang, R., Jin, Z., Liu, Z., Sun, L., Wang, L., and Li, K. (2011). Correlation of activated STAT3 expression with clinicopathologic features in lung adenocarcinoma and squamous cell carcinoma. Molecular diagnosis & therapy 15, 347-352.

Junior, R.F.D.A., Barboza, C.A.G., Clebis, N.K., de Moura, S.A., and Costa, A.D.L. (2008). Prognostic significance of the anatomical location and TNM clinical classification in oral squamous cell carcinoma. Med Oral Patol Oral 13, E344-E347.

Kawasaki, T., Kitsukawa, T., Bekku, Y., Matsuda, Y., Sanbo, M., Yagi, T., and Fujisawa, H. (1999). A requirement for neuropilin-1 in embryonic vessel formation. Development 126, 4895-4902.

Kitsukawa, T., Shimizu, M., Sanbo, M., Hirata, T., Taniguchi, M., Bekku, Y., Yagi, T., and Fujisawa, H. (1997). Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19, 995-1005.

Ko, Y.C., Huang, Y.L., Lee, C.H., Chen, M.J., Lin, L.M., and Tsai, C.C. (1995). Betel quid chewing, cigarette smoking and alcohol consumption related to oral cancer in Taiwan. Journal of oral pathology & medicine 24, 450-453.

Lam, W.K. (2005). Lung cancer in Asian women-the environment and genes. Respirology 10, 408-417.

Le Calvez, F., Mukeria, A., Hunt, J.D., Kelm, O., Hung, R.J., Taniere, P., Brennan, P., Boffetta, P., Zaridze, D.G., and Hainaut, P. (2005). TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: Distinct patterns in never, former, and current smokers. Cancer Res 65, 5076-5083.

Levy, D.E., and Lee, C.K. (2002). What does Stat3 do? The Journal of clinical investigation 109, 1143-1148.

Lian Ie, B., Tseng, Y.T., Su, C.C., and Tsai, K.Y. (2013). Progression of precancerous lesions to oral cancer: results based on the Taiwan National Health Insurance Database. Oral oncology 49, 427-430.

Lichtinghagen, R., Musholt, P.B., Lein, M., Romer, A., Rudolph, B., Kristiansen, G., Hauptmann, S., Schnorr, D., Loening, S.A., and Jung, K. (2002). Different mRNA and protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitor of metalloproteinases 1 in benign and malignant prostate tissue. European urology 42, 398-406.

Liu, C.Y., Hung, J.J., Wang, B.Y., Hsu, W.H., and Wu, Y.C. (2013a). Prognostic factors in resected pathological N1-stage II nonsmall cell lung cancer. The European respiratory journal 41, 649-655.

Liu, F., Cao, J., Wu, J., Sullivan, K., Shen, J., Ryu, B., Xu, Z., Wei, W., and Cui, R. (2013b). Stat3-targeted therapies overcome the acquired resistance to vemurafenib in melanomas. Journal of Investigative Dermatology 133, 2041-2049.

Lo, W.-Y., Tsai, M.-H., Tsai, Y., Hua, C.-H., Tsai, F.-J., Huang, S.-Y., Tsai, C.-H., and Lai, C.-C. (2007). Identification of over-expressed proteins in oral squamous cell carcinoma (OSCC) patients by clinical proteomic analysis. Clinica chimica acta 376, 101-107.

Lou, W., Ni, Z., Dyer, K., Tweardy, D.J., and Gao, A.C. (2000). Interleukin‐6 induces prostate cancer cell growth accompanied by activation of Stat3 signaling pathway. The prostate 42, 239-242.

Martello, L.A., McDaid, H.M., Regl, D.L., Yang, C.-P.H., Meng, D., Pettus, T.R., Kaufman, M.D., Arimoto, H., Danishefsky, S.J., and Smith, A.B. (2000). Taxol and discodermolide represent a synergistic drug combination in human carcinoma cell lines. Clinical Cancer Research 6, 1978-1987.

Matsushita, A., Götze, T., and Korc, M. (2007). Hepatocyte Growth Factor–Mediated Cell Invasion in Pancreatic Cancer Cells Is Dependent on Neuropilin-1. Cancer Res 67, 10309-10316.

Miao, H.-Q., LEE, P., LIN, H., SOKER, S., and KLAGSBRUN, M. (2000). Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. The FASEB journal 14, 2532-2539.

Mirsadraee, S., Oswal, D., Alizadeh, Y., Caulo, A., and van Beek, E., Jr. (2012). The 7th lung cancer TNM classification and staging system: Review of the changes and implications. World journal of radiology 4, 128-134.

Nakamura, F., and Goshima, Y. (2002). Structural and functional relation of neuropilins. In Neuropilin: From Nervous System to Vascular and Tumor Biology (Springer), pp. 55-69.

Nguyen, D.X., Bos, P.D., and Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer 9, 274-284.

Niu, G., Heller, R., Catlett-Falcone, R., Coppola, D., Jaroszeski, M., Dalton, W., Jove, R., and Yu, H. (1999). Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo. Cancer Res 59, 5059-5063.

Paez, J.G., Janne, P.A., Lee, J.C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F.J., Lindeman, N., Boggon, T.J., et al. (2004). EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304, 1497-1500.

Parker, M.W., Guo, H.-F., Li, X., Linkugel, A.D., and Vander Kooi, C.W. (2012). Function of members of the neuropilin family as essential pleiotropic cell surface receptors. Biochemistry 51, 9437-9446.

Sadowski, H.B., Shuai, K., Darnell, J.E., and Gilman, M.Z. (1993). A Common Nuclear Signal-Transduction Pathway Activated by Growth-Factor and Cytokine Receptors. Science 261, 1739-1744.



Sankaranarayanan, R., Masuyer, E., Swaminathan, R., Ferlay, J., and Whelan, S. (1998). Head and neck cancer: a global perspective on epidemiology and prognosis. Anticancer research 18, 4779-4786.


Schwanhausser, B., Busse, D., Li, N., Dittmar, G., Schuchhardt, J., Wolf, J., Chen, W., and Selbach, M. (2013). Corrigendum: Global quantification of mammalian gene expression control. Nature 495, 126-127.

Shaw, A.T., and Engelman, J.A. (2013). ALK in lung cancer: past, present, and future. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 31, 1105-1111.

Shaw, A.T., Kim, D.-W., Mehra, R., Tan, D.S.W., Felip, E., Chow, L.Q.M., Camidge, D.R., Vansteenkiste, J., Sharma, S., De Pas, T., et al. (2014). Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer. New England Journal of Medicine 370, 1189-1197.

Soker, S., Takashima, S., Miao, H.Q., Neufeld, G., and Klagsbrun, M. (1998). Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92, 735-745.

Song, J.I., and Grandis, J.R. (2000). STAT signaling in head and neck cancer. Oncogene 19, 2489-2495.

Stark, A.M., Pfannenschmidt, S., Tscheslog, H., Maass, N., Rosel, F., Mehdorn, H.M., and Held-Feindt, J. (2006). Reduced mRNA and protein expression of BCL-2 versus decreased mRNA and increased protein expression of BAX in breast cancer brain metastases: a real-time PCR and immunohistochemical evaluation. Neurological research 28, 787-793.

Su, C.C., Lin, Y.Y., Chang, T.K., Chiang, C.T., Chung, J.A., Hsu, Y.Y., and Lian Ie, B. (2010). Incidence of oral cancer in relation to nickel and arsenic concentrations in farm soils of patients' residential areas in Taiwan. BMC public health 10, 67.

Su, C.C., Yang, H.F., Huang, S.J., and Lian, I.B. (2007). Distinctive features of oral cancer in Changhua County: High incidence, buccal mucosa preponderance, and a close relation to betel quid chewing habit. J Formos Med Assoc 106, 225-233.

Sugahara, K.N., Teesalu, T., Karmali, P.P., Kotamraju, V.R., Agemy, L., Greenwald, D.R., and Ruoslahti, E. (2010). Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328, 1031-1035.

Takagi, S., Tsuji, T., Amagai, T., Takamatsu, T., and Fujisawa, H. (1987). Specific cell surface labels in the visual centers of Xenopus laevis tadpole identified using monoclonal antibodies. Developmental biology 122, 90-100.

Takeda, K., Noguchi, K., Shi, W., Tanaka, T., Matsumoto, M., Yoshida, N., Kishimoto, T., and Akira, S. (1997). Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proceedings of the National Academy of Sciences 94, 3801-3804.

Wahbah, M., Boroumand, N., Castro, C., El-Zeky, F., and Eltorky, M. (2007). Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Annals of diagnostic pathology 11, 89-96.

Wei, L.-H., Kuo, M.-L., Chen, C.-A., Chou, C.-H., Lai, K.-B., Lee, C.-N., and Hsieh, C.-Y. (2003). Interleukin-6 promotes cervical tumor growth by VEGF-dependent angiogenesis via a STAT3 pathway. Oncogene 22, 1517-1527.

Wey, J.S., Fan, F., Gray, M.J., Bauer, T.W., McCarty, M.F., Somcio, R., Liu, W., Evans, D.B., Wu, Y., Hicklin, D.J., et al. (2005). Vascular endothelial growth factor receptor-1 promotes migration and invasion in pancreatic carcinoma cell lines. Cancer 104, 427-438.

Yabuki, N., Sakata, K., Yamasaki, T., Terashima, H., Mio, T., Miyazaki, Y., Fujii, T., and Kitada, K. (2007). Gene amplification and expression in lung cancer cells with acquired paclitaxel resistance. Cancer genetics and cytogenetics 173, 1-9.

Yaqoob, U., Cao, S., Shergill, U., Jagavelu, K., Geng, Z., Yin, M., de Assuncao, T.M., Cao, Y., Szabolcs, A., and Thorgeirsson, S. (2012). Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res 72, 4047-4059.



Yu, H., Pardoll, D., and Jove, R. (2009). STATs in cancer inflammation and immunity: a leading role for STAT3. Nature Reviews Cancer 9, 798-809.

Zhang, S., Zhau, H.E., Osunkoya, A.O., Iqbal, S., Yang, X., Fan, S., Chen, Z., Wang, R., Marshall, F.F., Chung, L.W., et al. (2010). Vascular endothelial growth factor regulates myeloid cell leukemia-1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. Molecular cancer 9, 9.

Zheng, X., Wang, X., Mao, H., Wu, W., Liu, B., and Jiang, X. (2015). Hypoxia-specific ultrasensitive detection of tumours and cancer cells in vivo. Nature communications 6.
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2020-08-25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