(3.235.108.188) 您好!臺灣時間:2021/02/25 08:22
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果

詳目顯示:::

我願授權國圖
: 
twitterline
研究生:陳盈璇
研究生(外文):Ying-Shiuan Chen
論文名稱:探討Notch3訊息路徑在胃癌所扮演的角色
論文名稱(外文):Roles of Notch3 Signaling in Tumorigenesis of Gastric Cancer
指導教授:葉添順
指導教授(外文):Tien-Shun Yeh
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:解剖學及細胞生物學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2010
畢業學年度:98
語文別:中文
論文頁數:69
中文關鍵詞:胃癌Notch3受體
外文關鍵詞:Gastric CancerNotch3 receptor
相關次數:
  • 被引用被引用:0
  • 點閱點閱:165
  • 評分評分:系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔系統版面圖檔
  • 下載下載:8
  • 收藏至我的研究室書目清單書目收藏:1
胃癌是世界上常見的惡性腫瘤之一,有關胃癌癌化之分子機制仍混沌不清。引發胃癌之危險因子包括飲食、遺傳、幽門螺旋桿菌等,由於胃癌早期症狀不明顯,且易與胃潰瘍之病徵混淆,因此大多病患被診斷出胃癌,已是中後期之癌症,且有伴隨轉移到淋巴或其他器官,如肝臟、腹膜擴散等。對於胃癌的治療方式以摘除胃部組織及周邊淋巴腺廓清為主,合併放射治療及化學藥物治療,但其擴散及轉移之情形,仍導致胃癌之預後不佳。因此研究胃癌癌化之分子機制,作為早期診斷、分期病變及用藥方針現今的重要使命。Notch訊息路徑調控許多細胞內作用,包括增生、分化、凋亡、幹細胞之維持等,對腫瘤生成具有促進或抑制的影響。先前研究指出Notch1訊息路徑可藉由提升COX-2之表現促進胃癌癌化之過程。哺乳類有四種Notch受體蛋白,在結構上具有高度保留的現象,截至目前為止,不同的Notch訊息路徑對於胃癌癌化過程調控機制尚未明瞭。本論文探討Notch3訊息路徑在胃癌癌化過程中所扮演的角色。利用Tet-on系統建立可受doxycycline誘發而大量表現Notch3受體細胞內區域 (N3IC)於SC-M1人類胃腺癌細胞株。經由doxycycline誘發N3IC表現後,SC-M1胃腺癌細胞之增生能力受到抑制,且細胞中cyclin D1、cyclin D3、cyclin E、p21、p53等細胞週期調控蛋白表現量有提升之現象,然而以報導基因表現分析及蛋白質降解分析,發現N3IC可以增加p21轉錄活性並維持其蛋白穩定度。在腫瘤形成能力方面,SC-M1胃腺癌細胞誘發N3IC表現後,細胞群落形成能力被降低,以及皮下注射後之腫瘤生長受到抑制。此外,進一步研究發現SC-M1細胞之移行和侵襲能力也被N3IC所抑制。另一方面,利用AGS和NUGC-3胃癌細胞株進行移行和侵襲能力之分析,也同樣觀察到這些癌化之能力皆被N3IC所抑制。在調控下游基因功能方面,N3IC可以活化c-myc啟動子,並且其轉錄起始點P2區域扮演重要角色。總而言之,這些結果顯示Notch3訊息路徑抑制胃癌癌化過程。
Gastric carcinoma is one of the most common cancers and lethal malignancies worldwide. So far, the molecular mechanisms are still unclear. Salty foods, family history, and Helicobacter pylori infection are seem to higher rick of gastric cancer. The symptoms of early gastric cancer are similar to gastric ulcer or other stomach problems. Most patients were diagnosed with nearby lymph nodes metastasis or in late stage. Surgery followed by chemotherapy or radiotherapy is the most common treatment of gastric cancer. But the spread of lymph nodes and other organs frequently causes poor prognosis of gastric cancer. Therefore study of the molecular mechanism of gastric cancer is very important in modern medicine in the cause of diagnosis, pathogenesis and therapeutic strategies. Notch receptors may regulate cell functions such as proliferation, differentiation, apoptosis and stem cell maintenance. Notch receptors play important roles to modulate tumorigenesis as oncogenes or tumor suppressors. The activation of Notch1 signal pathway promotes gastric cancer progression through COX-2. The four mammalian Notch receptors (Notch1–4) are highly conserved type I transmembrane glycoproteins. The roles of distinct signalings activated by different Notch receptors are still poorly understood in gastric cancer progression. Herein, we sought to address whether Notch3 signaling is involved in control of gastric cancer progression. The Tet-On system expressing Notch3 receptor intracellular domain (N3IC), the activated form of Notch3 receptor, was established in human stomach adenocarcinoma SC-M1 cells. After treatment with doxycycline to induce N3IC expression, proliferation was inhibited in SC-M1 cells. Expressions of cell cycle-regulatory proteins were elevated by N3IC in SC-M1 cells such as cyclin D1, cyclin D3, cyclin E, p21 and p53. Furthermore, N3IC promoted p21 transcription activity and protein stability in SC-M1 cells. N3IC attenuated the xenografted tumor growth of SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by N3IC. Migration and invasion abilities of other gastric cancer cells were also suppressed by N3IC. Moreover, N3IC enhanced transcriptional activity of Notch downstream target gene c-Myc possibly through P2 transcription start site. Taken together, these results suggest that Notch3 signal pathway suppresses gastric cancer progression.
摘要 i
Abstract ii
縮寫表 iv
目錄 vi
前言 1
胃癌 1
Notch訊息路徑 3
材料 10
細胞株 10
實驗室建立之細胞株 10
質體 11
抗體 12
藥品及試劑 14
器材與儀器 16
引子 17
方法 18
一、細胞培養 18
細胞解凍活化 18
細胞繼代培養 18
細胞計數 19
細胞冷凍保存 20
二、西方點墨法 20
萃取細胞總蛋白質及定量 20
硫酸十二酯鈉聚丙烯醯胺凝膠 21
蛋白質電泳 21
蛋白質轉漬與免疫染色 22
化學發光偵測膜上蛋白 22
三、即時定量聚合酶鏈鎖反應 22
核醣核酸萃取 22
核醣核酸定量 23
核醣核酸反轉錄為去氧核醣核酸 23
即時定量聚合酶鏈鎖反應 24
四、短暫轉染 24
Electroporation短暫轉染法 24
SuperFect短暫轉染法 25
五、報導基因分析 25
六、細胞存活測試 26
七、細胞聚落形成能力試驗 26
八、老鼠移植腫瘤細胞模式 27
九、細胞移行能力試驗及侵襲能力試驗 27
細胞移行能力試驗 27
細胞侵襲能力試驗 28
十、蛋白質降解試驗 29
十一、統計分析 29
結果 30
一、 偵測不同人類胃腺癌細胞株內生性活化態Notch3受體蛋白表現 30
二、 誘導表現活化態Notch3受體之SC-M1胃腺癌細胞確實可以活化Notch訊息路徑 30
三、 表現活化態Notch3受體降低SC-M1胃腺癌細胞生長 31
四、 表現活化態Notch3受體可以調控p21轉錄活性以及蛋白穩度 31
五、 表現活化態Notch3受體抑制SC-M1胃腺癌細胞腫瘤形成能力 32
六、 表現活化態Notch3受體抑制SC-M1胃腺癌細胞轉移能力 32
七、 活化態Notch3受體對上皮間質細胞轉型重要標誌蛋白不具有顯著調控作用 33
八、 活化態Notch3受體可活化c-Myc轉錄活性 33
九、 於AGS及NUGC-3胃癌細胞株中表現活化態Notch3受體皆會抑制轉移之能力。 34
討論 35
參考資料 40
圖表與圖表說明 53
圖一、人類胃腺癌細胞株內生性活化態Notch3受體蛋白表現量 53
圖二、以doxycycline誘導SC-M1/N3IC-myc-His細胞株表現活化態Notch3受體 54
圖三、SC-M1胃腺癌細胞誘導表現活化態Notch3受體後可以活化細胞內Notch訊息路徑 55
圖四、表現活化態Notch3受體降低SC-M1胃腺癌細胞生長 56
圖五、表現活化態Notch3受體影響SC-M1胃腺癌細胞不同的細胞週期調控蛋 57
圖六、表現活化態Notch3受體可以調控p21轉錄活性以及蛋白穩定度 59
圖七、表現活化態Notch3受體抑制細胞群落形成能力 60
圖八、表現活化態Notch3受體抑制SC-M1胃腺癌細胞於裸鼠皮下腫瘤形成能 61
圖九、表現活化態Notch3受體抑制SC-M1胃腺癌細胞轉移能力 62
圖十、表現活化態Notch3受體促進SC-M1胃腺癌細胞傷口癒合能力 64
圖十一、表現活化態Notch3受體可抑制不同胃癌細胞轉移能力 65
圖十二、表現活化態Notch3受體使SC-M1細胞型態較為狹長 66
圖十三、表現活化態Notch3受體不影響SC-M1細胞的上皮間質細胞轉型重要標誌蛋白之表現 67
圖十四、表現活化態Notch3受體可以顯著活化c-Myc啟動子區域轉錄活性 68
圖十五、表現活化態Notch3受體皆可活化不同c-myc啟動子片段轉錄活性 69
Akiyama, J., and Uemura, N. (2009). Intestinal metaplasia subtype and gastric cancer risk. J. Gastroenterol. Hepatol. 24, 4-6.
Akiyama, S., Amo, H., Watanabe, T., Matsuyama, M., Sakamoto, J., Imaizumi, M., Ichihashi, H., Kondo, T., and Takagi, H. (1988). Characteristics of three human gastric cancer cell lines, NU-GC-2, NU-GC-3 and NU-GC-4. Jpn. J. Surg. 18, 438-446.
Alexson, T.O., Hitoshi, S., Coles, B.L., Bernstein, A., and van der Kooy, D. (2006). Notch signaling is required to maintain all neural stem cell populations--irrespective of spatial or temporal niche. Dev. Neurosci. 28, 34-48.
Amin, A.R., Patel, R.N., Thakker, G.D., Lowenstein, C.J., Attur, M.G., and Abramson, S.B. (1997). Post-transcriptional regulation of inducible nitric oxide synthase mRNA in murine macrophages by doxycycline and chemically modified tetracyclines. FEBS Lett. 410, 259-264.
Artavanis-Tsakonas, S., Rand, M.D., and Lake, R.J. (1999). Notch signaling: cell fate control and signal integration in development. Science 284, 770-776.
Barr, L.F., Campbell, S.E., Diette, G.B., Gabrielson, E.W., Kim, S., Shim, H., and Dang, C.V. (2000). c-Myc suppresses the tumorigenicity of lung cancer cells and down-regulates vascular endothelial growth factor expression. Cancer Res. 60, 143-149.
Barrantes, I.B., Elia, A.J., Wunsch, K., Hrabe de Angelis, M.H., Mak, T.W., Rossant, J., Conlon, R.A., Gossler, A., and de la Pompa, J.L. (1999). Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse. Curr. Biol. 9, 470-480.
Beatus, P., Lundkvist, J., Oberg, C., and Lendahl, U. (1999). The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters. Development 126, 3925-3935.
Beatus, P., Lundkvist, J., Oberg, C., Pedersen, K., and Lendahl, U. (2001). The origin of the ankyrin repeat region in Notch intracellular domains is critical for regulation of HES promoter activity. Mech. Dev. 104, 3-20.
Bellavia, D., Campese, A.F., Checquolo, S., Balestri, A., Biondi, A., Cazzaniga, G., Lendahl, U., Fehling, H.J., Hayday, A.C., Frati, L., et al. (2002). Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc. Natl. Acad. Sci. U S A 99, 3788-3793.
Bellavia, D., Checquolo, S., Campese, A.F., Felli, M.P., Gulino, A., and Screpanti, I. (2008). Notch3: from subtle structural differences to functional diversity. Oncogene 27, 5092-5098.
Belin de Chantemele, E.J., Retailleau, K., Pinaud, F., Vessieres, E., Bocquet, A., Guihot, A.L., Lemaire, B., Domenga, V., Baufreton, C., Loufrani, L., et al. (2008). Notch3 is a major regulator of vascular tone in cerebral and tail resistance arteries. Arterioscler Thromb. Vasc. Biol. 28, 2216-2224.
Bianchi, S., Dotti, M.T., and Federico, A. (2006). Physiology and pathology of notch signalling system. J. Cell Physiol. 207, 300-308.
Blankfield, R.P. (2002). Helicobacter pylori infection and the development of gastric cancer. N. Engl. J. Med. 346, 65-67.
Bourguet, W., Germain, P., and Gronemeyer, H. (2000). Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications. Trends Pharmacol. Sci. 21, 381-388.
Brou, C., Logeat, F., Gupta, N., Bessia, C., LeBail, O., Doedens, J.R., Cumano, A., Roux, P., Black, R.A., and Israel, A. (2000). A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol. Cell 5, 207-216.
Casariego Vales, E., Pita Fernandez, S., Rigueiro Veloso, M.T., Pertega Diaz, S., Rabunal Rey, R., Garcia-Rodeja, M.E., and Alvarez Cervela, L. (2001). Survival and prognostic factors for gastric cancer. Analysis of 2,334 patients. Med. Clin. (Barc) 117, 361-365.
Chiang, Y.M., Lo, C.P., Chen, Y.P., Wang, S.Y., Yang, N.S., Kuo, Y.H., and Shyur, L.F. (2005). Ethyl caffeate suppresses NF-kappaB activation and its downstream inflammatory mediators, iNOS, COX-2, and PGE2 in vitro or in mouse skin. Br. J. Pharmacol. 146, 352-363.
Chitnis, A. (2006). Why is delta endocytosis required for effective activation of notch? Dev. Dyn. 235, 886-894.
Choi, J.H., Park, J.T., Davidson, B., Morin, P.J., Shih Ie, M., and Wang, T.L. (2008). Jagged-1 and Notch3 juxtacrine loop regulates ovarian tumor growth and adhesion. Cancer Res. 68, 5716-5723.
de Manzoni, G., Verlato, G., Roviello, F., Morgagni, P., Di Leo, A., Saragoni, L., Marrelli, D., Kurihara, H., and Pasini, F. (2002). The new TNM classification of lymph node metastasis minimises stage migration problems in gastric cancer patients. Br. J. Cancer 87, 171-174.
De Vita, F., Vecchione, L., Galizia, G., Di Martino, N., Fabozzi, T., Catalano, G., Ciardiello, F., and Orditura, M. (2009). Perspectives in adjuvant therapy of gastric cancer. Oncology 77 Suppl 1, 38-42.
Deregowski, V., Gazzerro, E., Priest, L., Rydziel, S., and Canalis, E. (2006). Role of the RAM domain and ankyrin repeats on notch signaling and activity in cells of osteoblastic lineage. J. Bone Miner. Res. 21, 1317-1326.
Dimberg, A., Bahram, F., Karlberg, I., Larsson, L.G., Nilsson, K., and Oberg, F. (2002). Retinoic acid-induced cell cycle arrest of human myeloid cell lines is associated with sequential down-regulation of c-Myc and cyclin E and posttranscriptional up-regulation of p27(Kip1). Blood 99, 2199-2206.
Doucas, H., Mann, C.D., Sutton, C.D., Garcea, G., Neal, C.P., Berry, D.P., and Manson, M.M. (2008). Expression of nuclear Notch3 in pancreatic adenocarcinomas is associated with adverse clinical features, and correlates with the expression of STAT3 and phosphorylated Akt. J. Surg. Oncol. 97, 63-68.
Efstratiadis, A., Szabolcs, M., and Klinakis, A. (2007). Notch, Myc and breast cancer. Cell Cycle 6, 418-429.
El, H., II, Hashash, J.G., Baz, E.M., Abdul-Baki, H., and Sharara, A.I. (2007). ABO blood group and gastric cancer: rekindling an old fire? South Med. J. 100, 726-727.
Farrell, J.J. (2009). "Adjuvant" therapy after endoscopic mucosal resection of early gastric cancer. Gastroenterology 137, 377-379.
Fuchs, C.S., and Mayer, R.J. (1995). Gastric carcinoma. N. Engl. J. Med. 333, 32-41.
Fujikura, J., Hosoda, K., Iwakura, H., Tomita, T., Noguchi, M., Masuzaki, H., Tanigaki, K., Yabe, D., Honjo, T., and Nakao, K. (2006). Notch/Rbp-j signaling prevents premature endocrine and ductal cell differentiation in the pancreas. Cell Metab. 3, 59-65.
Giovannini, C., Gramantieri, L., Chieco, P., Minguzzi, M., Lago, F., Pianetti, S., Ramazzotti, E., Marcu, K.B., and Bolondi, L. (2009). Selective ablation of Notch3 in HCC enhances doxorubicin's death promoting effect by a p53 dependent mechanism. J. Hepatol. 50, 969-979.
Guan, E., Wang, J., Laborda, J., Norcross, M., Baeuerle, P.A., and Hoffman, T. (1996). T cell leukemia-associated human Notch/translocation-associated Notch homologue has I kappa B-like activity and physically interacts with nuclear factor-kappa B proteins in T cells. J. Exp. Med. 183, 2025-2032.
Harrison, H., Farnie, G., Howell, S.J., Rock, R.E., Stylianou, S., Brennan, K.R., Bundred, N.J., and Clarke, R.B. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer. Res. 70, 709-718.
Hillen, W., Schollmeier, K., and Gatz, C. (1984). Control of expression of the Tn10-encoded tetracycline resistance operon. II. Interaction of RNA polymerase and TET repressor with the tet operon regulatory region. J. Mol. Biol. 172, 185-201.
Hsu, K.W., Hsieh, R.H., Lee, Y.H., Chao, C.H., Wu, K.J., Tseng, M.J., and Yeh, T.S. (2008). The activated Notch1 receptor cooperates with alpha-enolase and MBP-1 in modulating c-myc activity. Mol. Cell. Biol. 28, 4829-4842.
Indraccolo, S., Minuzzo, S., Masiero, M., Pusceddu, I., Persano, L., Moserle, L., Reboldi, A., Favaro, E., Mecarozzi, M., Di Mario, G., et al. (2009). Cross-talk between tumor and endothelial cells involving the Notch3-Dll4 interaction marks escape from tumor dormancy. Cancer Res. 69, 1314-1323.
Iso, T., Sartorelli, V., Poizat, C., Iezzi, S., Wu, H.Y., Chung, G., Kedes, L., and Hamamori, Y. (2001). HERP, a novel heterodimer partner of HES/E(spl) in Notch signaling. Mol. Cell. Biol. 21, 6080-6089.
Itoh, M., Fu, L., and Tohda, S. (2009). NF-kappaB activation induced by Notch ligand stimulation in acute myeloid leukemia cells. Oncol Rep 22, 631-634.
Izzo, M.W., Strachan, G.D., Stubbs, M.C., and Hall, D.J. (1999). Transcriptional repression from the c-myc P2 promoter by the zinc finger protein ZF87/MAZ. J. Biol. Chem. 274, 19498-19506.
Jarriault, S., Le Bail, O., Hirsinger, E., Pourquie, O., Logeat, F., Strong, C.F., Brou, C., Seidah, N.G., and Isra l, A. (1998). Delta-1 activation of notch-1 signaling results in HES-1 transactivation. Mol. Cell. Biol. 18, 7423-7431.
Jeffries, S., and Capobianco, A.J. (2000). Neoplastic transformation by Notch requires nuclear localization. Mol. Cell. Biol. 20, 3928-3941.
Joutel, A., Andreux, F., Gaulis, S., Domenga, V., Cecillon, M., Battail, N., Piga, N., Chapon, F., Godfrain, C., and Tournier-Lasserve, E. (2000). The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J. Clin. Invest. 105, 597-605.
Joutel, A., Corpechot, C., Ducros, A., Vahedi, K., Chabriat, H., Mouton, P., Alamowitch, S., Domenga, V., Cecillion, M., Marechal, E., et al. (1996). Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383, 707-710.
Kao, H.Y., Ordentlich, P., Koyano-Nakagawa, N., Tang, Z., Downes, M., Kintner, C.R., Evans, R.M., and Kadesch, T. (1998). A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. Genes Dev. 12, 2269-2277.
Katoh, M. (2005). Epithelial-mesenchymal transition in gastric cancer (Review). Int. J. Oncol. 27, 1677-1683.
Katoh, M. (2007). Notch signaling in gastrointestinal tract (review). Int. J. Oncol. 30, 247-251.
Kikuchi, S., Nemoto, Y., Katada, N., Sakuramoto, S., Kobayashi, N., Shimao, H., Sakakibara, Y., and Kakita, A. (2002). Clinical evaluation of pN-stage (TNM) in gastric cancer: an analysis of distribution of regional lymph nodes in node-positive patients. Anticancer Res. 22, 1141-1144.
Klueg, K.M., and Muskavitch, M.A. (1999). Ligand-receptor interactions and trans-endocytosis of Delta, Serrate and Notch: members of the Notch signalling pathway in Drosophila. J. Cell Sci. 112 ( Pt 19), 3289-3297.
Koeffler, H.P., and Golde, D.W. (1980). Human myeloid leukemia cell lines: a review. Blood 56, 344-350.
Konishi, J., Kawaguchi, K.S., Vo, H., Haruki, N., Gonzalez, A., Carbone, D.P., and Dang, T.P. (2007). Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res. 67, 8051-8057.
Krebs, L.T., Xue, Y., Norton, C.R., Sundberg, J.P., Beatus, P., Lendahl, U., Joutel, A., and Gridley, T. (2003). Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation. Genesis 37, 139-143.
Kurtenkov, O., Klaamas, K., and Miljukhina, L. (1995). The lower level of natural anti-Thomsen-Friedenreich antigen (TFA) agglutinins in sera of patients with gastric cancer related to ABO(H) blood-group phenotype. Int. J. Cancer 60, 781-785.
Lai, E.C. (2002). Keeping a good pathway down: transcriptional repression of Notch pathway target genes by CSL proteins. EMBO Rep. 3, 840-845.
Lake, R.J., Grimm, L.M., Veraksa, A., Banos, A., and Artavanis-Tsakonas, S. (2009). In vivo analysis of the Notch receptor S1 cleavage. PLoS One 4, e6728.
Lamar, E., Deblandre, G., Wettstein, D., Gawantka, V., Pollet, N., Niehrs, C., and Kintner, C. (2001). Nrarp is a novel intracellular component of the Notch signaling pathway. Genes Dev. 15, 1885-1899.
Lardelli, M., Dahlstrand, J., and Lendahl, U. (1994). The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech. Dev. 46, 123-136.
Lee, K.E., Lee, H.J., Kim, Y.H., Yu, H.J., Yang, H.K., Kim, W.H., Lee, K.U., Choe, K.J., and Kim, J.P. (2003). Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer. Jpn. J. Clin. Oncol. 33, 173-179.
Leong, K.G., and Karsan, A. (2006). Recent insights into the role of Notch signaling in tumorigenesis. Blood 107, 2223-2233.
Liu, H., Kennard, S., and Lilly, B. (2009). NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ. Res. 104, 466-475.
Macleod, K.F., Sherry, N., Hannon, G., Beach, D., Tokino, T., Kinzler, K., Vogelstein, B., and Jacks, T. (1995). p53-dependent and independent expression of p21 during cell growth, differentiation, and DNA damage. Genes. Dev. 9, 935-944.
Marchal, C., Haguenauer-Tsapis, R., and Urban-Grimal, D. (1998). A PEST-like sequence mediates phosphorylation and efficient ubiquitination of yeast uracil permease. Mol. Cell. Biol. 18, 314-321.
Martinez Arias, A., Zecchini, V., and Brennan, K. (2002). CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr. Opin. Genet. Dev. 12, 524-533.
McConnell, B.B., Gregory, F.J., Stott, F.J., Hara, E., and Peters, G. (1999). Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol. Cell. Biol. 19, 1981-1989.
McDaniell, R., Warthen, D.M., Sanchez-Lara, P.A., Pai, A., Krantz, I.D., Piccoli, D.A., and Spinner, N.B. (2006). NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am. J. Hum. Genet. 79, 169-173.
Meek, D.W. (2009). Tumour suppression by p53: a role for the DNA damage response? Nat. Rev. Cancer 9, 714-723.
Moberg, K.H., Tyndall, W.A., Pyrc, J., and Hall, D.J. (1991). Analysis of the c-myc P2 promoter. J. Cell. Physiol. 148, 75-84.
Munro, S., and Freeman, M. (2000). The notch signalling regulator fringe acts in the Golgi apparatus and requires the glycosyltransferase signature motif DXD. Curr. Biol. 10, 813-820.
Nanbru, C., Prats, A.C., Droogmans, L., Defrance, P., Huez, G., and Kruys, V. (2001). Translation of the human c-myc P0 tricistronic mRNA involves two independent internal ribosome entry sites. Oncogene 20, 4270-4280.
Niessen, K., Fu, Y., Chang, L., Hoodless, P.A., McFadden, D., and Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. J. Cell. Biol. 182, 315-325.
Noseda, M., Chang, L., McLean, G., Grim, J.E., Clurman, B.E., Smith, L.L., and Karsan, A. (2004). Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression. Mol. Cell. Biol. 24, 8813-8822.
Noseda, M., Fu, Y., Niessen, K., Wong, F., Chang, L., McLean, G., and Karsan, A. (2006). Smooth Muscle alpha-actin is a direct target of Notch/CSL. Circ. Res. 98, 1468-1470.
O'Neill, C.F., Urs, S., Cinelli, C., Lincoln, A., Nadeau, R.J., Leon, R., Toher, J., Mouta-Bellum, C., Friesel, R.E., and Liaw, L. (2007). Notch2 signaling induces apoptosis and inhibits human MDA-MB-231 xenograft growth. Am. J. Pathol. 171, 1023-1036.
Oh, S.Y., Kwon, H.C., Kim, S.H., Jang, J.S., Kim, M.C., Kim, K.H., Han, J.Y., Kim, C.O., Kim, S.J., Jeong, J.S., et al. (2008). Clinicopathologic significance of HIF-1alpha, p53, and VEGF expression and preoperative serum VEGF level in gastric cancer. BMC Cancer 8, 123.
Okusa, Y., Shinomiya, N., Ichikura, T., and Mochizuki, H. (1998). Correlation between telomerase activity and DNA ploidy in gastric cancer. Oncology 55, 258-264.
Ong, C.T., Cheng, H.T., Chang, L.W., Ohtsuka, T., Kageyama, R., Stormo, G.D., and Kopan, R. (2006). Target selectivity of vertebrate notch proteins. Collaboration between discrete domains and CSL-binding site architecture determines activation probability. J. Biol. Chem. 281, 5106-5119.
Onoda, T., Ono, T., Dhar, D.K., Yamanoi, A., and Nagasue, N. (2006). Tetracycline analogues (doxycycline and COL-3) induce caspase-dependent and -independent apoptosis in human colon cancer cells. Int. J. Cancer 118, 1309-1315.
Oswald, F., Kostezka, U., Astrahantseff, K., Bourteele, S., Dillinger, K., Zechner, U., Ludwig, L., Wilda, M., Hameister, H., Knochel, W., et al. (2002). SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO J. 21, 5417-5426.
Park, J.M., Kim, J.H., Park, S.S., Kim, S.J., Mok, Y.J., and Kim, C.S. (2008). Prognostic factors and availability of D2 lymph node dissection for the patients with stage II gastric cancer: comparative analysis of subgroups in stage II. World J. Surg. 32, 1037-1044.
Pluck, A. (1996). Conditional mutagenesis in mice: the Cre/loxP recombination system. Int. J. Exp. Pathol. 77, 269-278.
Radtke, F., and Raj, K. (2003). The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat. Rev. Cancer 3, 756-767.
Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M., Mammucari, C., Oh, H., Aster, J.C., Krishna, S., Metzger, D., Chambon, P., et al. (2001). Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 20, 3427-3436.
Rank, G.H., Arndt, G.M., and Xiao, W. (1989). FLP-FRT mediated intrachromosomal recombination on a tandemly duplicated YEp integrant at the ILV2 locus of chromosome XIII in Saccharomyces cerevisiae. Curr. Genet. 15, 107-112.
Rechsteiner, M. (1988). Regulation of enzyme levels by proteolysis: the role of pest regions. Adv. Enzyme Regul. 27, 135-151.
Reedijk, M., Odorcic, S., Chang, L., Zhang, H., Miller, N., McCready, D.R., Lockwood, G., and Egan, S.E. (2005). High-level coexpression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res. 65, 8530-8537.
Ronchini, C., and Capobianco, A.J. (2001). Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol. Cell. Biol. 21, 5925-5934.
Rosivatz, E., Becker, I., Specht, K., Fricke, E., Luber, B., Busch, R., Hofler, H., and Becker, K.F. (2002). Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am. J. Pathol. 161, 1881-1891.
Ross, D.A., Rao, P.K., and Kadesch, T. (2004). Dual roles for the Notch target gene Hes-1 in the differentiation of 3T3-L1 preadipocytes. Mol. Cell. Biol. 24, 3505-3513.
Sapadin, A.N., and Fleischmajer, R. (2006). Tetracyclines: nonantibiotic properties and their clinical implications. J. Am. Acad. Dermatol. 54, 258-265.
Sarmento, L.M., Huang, H., Limon, A., Gordon, W., Fernandes, J., Tavares, M.J., Miele, L., Cardoso, A.A., Classon, M., and Carlesso, N. (2005). Notch1 modulates timing of G1-S progression by inducing SKP2 transcription and p27 Kip1 degradation. J. Exp. Med. 202, 157-168.
Schmitt, T.M., Ciofani, M., Petrie, H.T., and Zuniga-Pflucker, J.C. (2004). Maintenance of T cell specification and differentiation requires recurrent notch receptor-ligand interactions. J. Exp. Med. 200, 469-479.
Sekiguchi, M., Sakakibara, K., and Fujii, G. (1978). Establishment of cultured cell lines derived from a human gastric carcinoma. Jpn. J. Exp. Med. 48, 61-68.
Sengupta, A., Banerjee, D., Chandra, S., Banerji, S.K., Ghosh, R., Roy, R., and Banerjee, S. (2007). Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. Leukemia 21, 949-955.
Shikata, K., Kiyohara, Y., Kubo, M., Yonemoto, K., Ninomiya, T., Shirota, T., Tanizaki, Y., Doi, Y., Tanaka, K., Oishi, Y., et al. (2006). A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study. Int. J. Cancer 119, 196-201.
Shimakura, S., and Boland, C.R. (1992). Eicosanoid production by the human gastric cancer cell line AGS and its relation to cell growth. Cancer Res. 52, 1744-1749.
Shin, V.Y., Wu, W.K., Chu, K.M., Wong, H.P., Lam, E.K., Tai, E.K., Koo, M.W., and Cho, C.H. (2005). Nicotine induces cyclooxygenase-2 and vascular endothelial growth factor receptor-2 in association with tumor-associated invasion and angiogenesis in gastric cancer. Mol. Cancer Res. 3, 607-615.
Smith, G.N., Jr., Mickler, E.A., Hasty, K.A., and Brandt, K.D. (1999). Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme. Arthritis Rheum. 42, 1140-1146.
Sriuranpong, V., Borges, M.W., Ravi, R.K., Arnold, D.R., Nelkin, B.D., Baylin, S.B., and Ball, D.W. (2001). Notch signaling induces cell cycle arrest in small cell lung cancer cells. Cancer Res. 61, 3200-3205.
Tagami, S., Okochi, M., Yanagida, K., Ikuta, A., Fukumori, A., Matsumoto, N., Ishizuka-Katsura, Y., Nakayama, T., Itoh, N., Jiang, J., et al. (2008). Regulation of Notch signaling by dynamic changes in the precision of S3 cleavage of Notch-1. Mol. Cell. Biol. 28, 165-176.
Taki, T., Ishikawa, H., Imai, K., Yachi, A., and Matsumoto, M. (1985). Immunological analysis of glycolipids on cell surfaces of cultured human tumor cell lines: expression of lactoneotetraosylceramide on tumor cell surfaces. J. Biochem. 98, 887-895.
Tezuka, K., Yasuda, M., Watanabe, N., Morimura, N., Kuroda, K., Miyatani, S., and Hozumi, N. (2002). Stimulation of osteoblastic cell differentiation by Notch. J. Bone Miner. Res. 17, 231-239.
Tsugane, S., and Sasazuki, S. (2007). Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer 10, 75-83.
Turkdogan, M.K., Testereci, H., Akman, N., Kahraman, T., Kara, K., Tuncer, I., and Uygan, I. (2003). Dietary nitrate and nitrite levels in an endemic upper gastrointestinal (esophageal and gastric) cancer region of Turkey. Turk. J. Gastroenterol. 14, 50-53.
Tzeng, C.C., Meng, C.L., Jin, L., and Hsieh, H.F. (1991). Cytogenetic studies of gastric adenocarcinoma. Cancer Genet. Cytogenet. 55, 67-71.
Uitto, V.J., Firth, J.D., Nip, L., and Golub, L.M. (1994). Doxycycline and chemically modified tetracyclines inhibit gelatinase A (MMP-2) gene expression in human skin keratinocytes. Ann. N. Y. Acad. Sci. 732, 140-151.
van Es, J.H., van Gijn, M.E., Riccio, O., van den Born, M., Vooijs, M., Begthel, H., Cozijnsen, M., Robine, S., Winton, D.J., Radtke, F., et al. (2005). Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells. Nature 435, 959-963.
Vardar, D., North, C.L., Sanchez-Irizarry, C., Aster, J.C., and Blacklow, S.C. (2003). Nuclear magnetic resonance structure of a prototype Lin12-Notch repeat module from human Notch1. Biochemistry 42, 7061-7067.
Veeraraghavalu, K., Pett, M., Kumar, R.V., Nair, P., Rangarajan, A., Stanley, M.A., and Krishna, S. (2004). Papillomavirus-mediated neoplastic progression is associated with reciprocal changes in JAGGED1 and manic fringe expression linked to notch activation. J. Virol. 78, 8687-8700.
Weijzen, S., Zlobin, A., Braid, M., Miele, L., and Kast, W.M. (2003). HPV16 E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation. J. Cell Physiol. 194, 356-362.
Wharton, K.A., Johansen, K.M., Xu, T., and Artavanis-Tsakonas, S. (1985). Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43, 567-581.
Wianny, F., Real, F.X., Mummery, C.L., Van Rooijen, M., Lahti, J., Samarut, J., and Savatier, P. (1998). G1-phase regulators, cyclin D1, cyclin D2, and cyclin D3: up-regulation at gastrulation and dynamic expression during neurulation. Dev. Dyn. 212, 49-62.
Wu, L., and Griffin, J.D. (2004). Modulation of Notch signaling by mastermind-like (MAML) transcriptional co-activators and their involvement in tumorigenesis. Semin. Cancer Biol. 14, 348-356.
Yamagata, R., Shimoyama, T., Fukuda, S., Yoshimura, T., Tanaka, M., and Munakata, A. (2002). Cyclooxygenase-2 expression is increased in early intestinal-type gastric cancer and gastric mucosa with intestinal metaplasia. Eur. J. Gastroenterol. Hepatol. 14, 359-363.
Yamaguchi, N., Oyama, T., Ito, E., Satoh, H., Azuma, S., Hayashi, M., Shimizu, K., Honma, R., Yanagisawa, Y., Nishikawa, A., et al. (2008). NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells. Cancer Res. 68, 1881-1888.
Yeh, T.S., Lin, Y.M., Hsieh, R.H., and Tseng, M.J. (2003). Association of transcription factor YY1 with the high molecular weight Notch complex suppresses the transactivation activity of Notch. J. Biol. Chem. 278, 41963-41969.
Yeh, T.S., Wu, C.W., Hsu, K.W., Liao, W.J., Yang, M.C., Li, A.F., Wang, A.M., Kuo, M.L., and Chi, C.W. (2009). The activated Notch1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2. Cancer Res. 69, 5039-5048.
Yuasa, Y. (2003). Control of gut differentiation and intestinal-type gastric carcinogenesis. Nat. Rev. Cancer 3, 592-600.
Yuasa, Y., Nagasaki, H., Akiyama, Y., Sakai, H., Nakajima, T., Ohkura, Y., Takizawa, T., Koike, M., Tani, M., Iwai, T., et al. (2005). Relationship between CDX2 gene methylation and dietary factors in gastric cancer patients. Carcinogenesis 26, 193-200.

連結至畢業學校之論文網頁點我開啟連結
註: 此連結為研究生畢業學校所提供,不一定有電子全文可供下載,若連結有誤,請點選上方之〝勘誤回報〞功能,我們會盡快修正,謝謝!
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top
系統版面圖檔 系統版面圖檔