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系統識別號 U0026-1001201311295500
論文名稱(中文) 在幽門桿菌感染的胃上皮細胞株中miR-21和miR-200a/b調控beta-catenin核內累積中所扮演的角色
論文名稱(英文) The regulatory role of miR-21 and miR-200a/b on nuclear accumulation of beta-catenin in H. pylori-infected gastric epithelial cell lines
校院名稱 成功大學
系所名稱(中) 分子醫學研究所
系所名稱(英) Institute of Molecular Medicine
學年度 101
學期 1
出版年 102
研究生(中文) 吳姿慧
研究生(英文) Zih-Huei Wu
學號 t16991070
學位類別 碩士
語文別 中文
論文頁數 94頁
口試委員 指導教授-呂政展
指導教授-許博翔
口試委員-吳俊忠
口試委員-呂佩融
中文關鍵字 幽門桿菌  miR-200a  miR-21  beta-catenin 
英文關鍵字 H. pylori  miR-21  miR-200a  beta-catenin 
學科別分類
中文摘要 幽門桿菌是導致胃癌最主要的原因,其中胃黏膜化生(Intestinal metaplasi, IM)為最著名的癌前病變。微小RNA (MicroRNAs)是後轉錄調節因子,在腫瘤生成中扮演重要的角色。腸黏膜化生特性之一,胃上皮細胞的細胞核中beta-catenin有過度表現的情況。MiR-200a已知可與beta-catenin的3端非轉譯區結合而降低其表現量。先前研究指出當幽門桿菌感染,miR-200a的表現量會下降。我們假設幽門桿菌感染之後,miR-200a會下降,而導致細胞中的beta-catenin上升,進而增加細胞核中beta-catenin的累積。為了驗證其可能性,我們將幽門桿菌與胃上皮細胞株進行共培養,在2、6和24小時收取樣品進行西方墨點法分析,分別為細胞裂解液和核質分離的裂解液;而miR-200a與其前趨物,pri-、pre和miR-200a皆使用即時定量聚合酶反應來定量。MiR-21先前研究中指出能影響WNT訊息路徑,且在胃癌中扮演角色,也偵測其前趨物和成熟的miRNA表現量。為了探討幽門桿菌中的致病因子是否參與miRNA調控的胃癌化生成,將菌株中特定的毒子因子破壞,接著探討其對miR-200a表現的影響。使用MKN45胃上皮細胞株,當感染幽門桿菌2和6小時後,miR-200a表現量下降,然而感染24小時後其表現量漸漸的回復到正常狀態。而miR-200a表現量下降將會導致beta-catenin表現量上升,其增加的beta-catenin優先的進入核中使其表現量上升,因此也增加了beta-catenin-LEF/TCF報導基因的活性。為了證實miR-200a對於beta-catenin調節的專一性,於MKN45細胞株中,使miR-200a過度表現,並且加入幽門桿菌感染,其結果發現因miR-200a大量表現,beta-catenin的表現量進而被抵消。為了了解mature miR-200a下降的機制,miR-200a的前驅物:pri-和pre- miR-200a也利用了即時定量聚合酶反應定量。在感染過程中,miR-200a與其前趨物有個複雜的、動態的變化。為了避免漣漪效應和可能的細菌致病因子結抗作用,我鎖定在感染後2個小時。在MKN45感染菌株J99中,pri-miR-200a和pre-miR-200a有一平行的變化,雖然在菌株27中沒有如此顯著。miR-200a表現量下降最主要是因為pri-miR-200a表現量受到抑制。由於miR-200b/a/429是由同一polycistronic transcript轉錄出來,我們也一併偵測了miR-200b的表現量。而抑制miR-200b/a/429 primary transcripts並非由ZEB1和SIP1轉錄抑制子所導致。反之,AGS胃上皮細胞株當幽門桿菌感染後pri-和miR-200a都有上升的情況。然而,miR-200a的上升並沒有導致beta-catenin表現量下降,而感染期間beta-catenin也沒有顯著的改變。此外,與幽門桿菌突變株共培養可導致pri-miR-200a表現量改變,推測CagA、VacA或是BabA參與miR-200b/a/429 primary transcripts的生成。總結如下,從這些研究中我有以下新的發現 (i) 在幽門桿菌感染的胃上皮細胞株,miR-200a的表現量下降,進而導致細胞核中的beta-catenin增加;(ii) miR-200a表現量下降是因為pri-200b/a/429 primary transcripts表現量下降;(iii) 而pri-200b/a/429 primary transcripts表現量下降並非是先前研究提到中受到轉錄抑制子ZEB1和SIP1的調控;(iv) 致病因子,例:CagA,VacA和BabA,皆有參與miR-200a的生成。
英文摘要 H. pylori is the major cause of gastric adenocarcinoma, of which intestinal metaplasia (IM) is a well-known gastric precancerous lesion. MicroRNAs (miRNAs) are post-transcriptional regulators that play important roles in tumorigenesis. One of the characteristic changes of intestinal metaplasia is the overexpression of beta-catenin within the nucleus of gastric epithelium. MiR-200a is known to bind to 3’UTR of beta-catenin to downregulate its expression. It has been reported that during H. pylori infection, the levels of miR-200a were reduced. We hypothesized that decreased levels of miR-200a during H. pylori infection may lead to the increase of total cellular beta-catenin, which subsequently result in nuclear accumulation of beta-catenin. To examine this possibility, H. pylori was co-cultured with gastric epithelial cell lines, at 2 hr, 6 hr and 24 hr postinfection, the total cellular and subcellular fraction of beta-catenin levels were analyzed by western blot and the amounts of miR-200a and its precursors, pri- miR-200a, pre-miR-200a were analyzed by real-time quantitative PCR. MiR-21 previously shown to affect the WNT signal pathway and play a role in gastric carcinogenesis was also analyzed for the expression of mature and precursor forms. To examine if bacterial virulence factors may be involved in miRNA-regulated gastric tumorigenesis, bacteria defective for specific factors were also investigated for their effects on miR-200a expression. At 2 hr and 6 hr postinfection in MKN45 cells, there is a reduced expression of miR-200a and gradually return to near normal levels at 24 hr postinfection. The reduced expression of miR-200a has resulted in the increase of total beta-catenin levels, which in turn led to the preferential nuclear accumulation of beta-catenin, thus increased beta-catenin- TCF/LEF-mediated reporter gene activity. The regulatory effect of miR-200a on beta-catenin in MKN45 is specific as the overexpression of miR-200a would counteract the increased beta-catenin levels imposed by H. pylori infection. To examine the mechanism by which the mature miR-200a decreased, the precursors of miR-200a, pri-miR-200a and pre-miR-200a, were also quantitated by real-time PCR. Over the course of infection, there is a complex, dynamic change of miR-200a and its precursors. To avoid the rippling effect and possible antagonistic effect of bacterial factors, I focused on the 2 hr post infection. A parallel change of pri-miR-200a and miR-200a expression levels was observed in MKN45 infected with strain J99, although it is less pronounced with strain 27. The reduced expression of miR-200a mainly resulted from the repressed expression of pri-miR-200a as the mature miR-200a has the same amount as that of the pri-miR-200a. Because miR-200b, miR-200a, and miR-429 are encoded by a single polycistronic transcript, we also detected miR-200b expression. The repressed generation of miR-200b/a/429 primary transcripts was not due to the induction of transcription repressors, ZEB1 and SIP1. In contrast, AGS cells infected with the same H. pylori strain had increase of both pri-miR-200a and miR-200a. However, the resulting increase of miR-200a did not lead to the decrease of total beta-catenin levels. Instead, over the course of 24 hr infection, the total beta-catenin did not have remarkable change. Moreover, co-culture with H. pylori defective for CagA, VacA or BabA has resulted in altered expression of pri-miR-200a, suggesting that CagA, VacA or BabA might be involved in regulating production of miR-200b/a/429 primary transcripts. In conclusion, from this study I have uncovered several novel findings (i) in H. pylori- infected gastric epithelium cell line, the generation of miR-200a has decreased miR-200a, which leads to the preferential accumulation beta-catenin within the nucleus, (ii) the decreased generation of miR-200a results from the reduced production of pri-miR-200b/a/429 primary transcripts, (iii) the repressed production of pri-miR-200b/a/429 primary transcripts was not due to the induction of transcription repressors, ZEB1 and SIP1 as previously reported, (iv) virulence factors, eg, CagA, VacA and BabA2, are involved in the regulation of miR-200a production.
論文目次 中文摘要 I
Abstract IV
致謝 VII
目錄 IX
緒論 1
材料與方法 14
結果 25
討論 33
參考文獻 43
表格 57
結果圖 58
附錄 77
參考文獻 Aberle, H., A. Bauer, J. Stappert, A. Kispert and R. Kemler (1997). "β-catenin is a target for the ubiquitin–proteasome pathway." EMBO J 16(13): 3797-3804.

Ahmad, A., Y. Govil and B. B. Frank (2003). "Gastric mucosa-associated lymphoid tissue lymphoma." The American journal of gastroenterology 98(5): 975-986.

Asangani, I., S. Rasheed, D. Nikolova, J. Leupold, N. Colburn, S. Post and H. Allgayer (2007). "MicroRNA-21 (miR-21) post-transcriptionally downregulates tumor suppressor Pdcd4 and stimulates invasion, intravasation and metastasis in colorectal cancer." Oncogene 27(15): 2128-2136.

Aspholm-Hurtig, M., G. Dailide, M. Lahmann, A. Kalia, D. Ilver, N. Roche, S. Vikström, R. Sjöström, S. Lindén and A. Bäckström (2004). "Functional adaptation of BabA, the H. pylori ABO blood group antigen binding adhesin." Science 305(5683): 519-522.

Bartel, D. P. (2004). "MicroRNAs: genomics, biogenesis, mechanism, and function." Cell 116(2): 281-297.

Baskerville, S. and D. P. Bartel (2005). "Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes." RNA 11(3): 241-247.

Behrens, J., J. P. von Kries, M. Kühl, L. Bruhn, D. Wedlich, R. Grosschedl and W. Birchmeier (1996). "Functional interaction of β-catenin with the transcription factor LEF-1." Nature 382(6592): 638-642.

Bernstein, E., A. A. Caudy, S. M. Hammond and G. J. Hannon (2001). "Role for a bidentate ribonuclease in the initiation step of RNA interference." Nature 409(6818): 363-365.

Bizzozero, G. (1893). "Ueber die schlauchförmigen Drüsen des Magendarmkanals und die Beziehungen ihres Epithels zu dem Oberflächenepithel der Schleimhaut Dritte Mittheilung." Archiv für mikroskopische Anatomie 42(1): 82-152.

Blaser, M. and J. Parsonnet (1994). "Parasitism by the" slow" bacterium Helicobacter pylori leads to altered gastric homeostasis and neoplasia." Journal of Clinical Investigation 94(1): 4.

Blaser, M. J. (1993). "Helicobacter pylori: microbiology of a 'slow' bacterial infection." Trends in microbiology 1(7): 255.

Borchert, G. M., W. Lanier and B. L. Davidson (2006). "RNA polymerase III transcribes human microRNAs." Nature structural & molecular biology 13(12): 1097-1101.

Boren, T., P. Falk, K. A. Roth, G. Larson and S. Normark (1993). "Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens." Science (New York, NY) 262(5141): 1892.

Bottoni, A., D. Piccin, F. Tagliati, A. Luchin, M. C. Zatelli and E. C. degli Uberti (2005). "miR-15a and miR-16-1 down-regulation in pituitary adenomas." J Cell Physiol 204(1): 280-285.

Bracken, C. P., P. A. Gregory, N. Kolesnikoff, A. G. Bert, J. Wang, M. F. Shannon and G. J. Goodall (2008). "A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition." Cancer Res 68(19): 7846-7854.

Calin, G. A., C. D. Dumitru, M. Shimizu, R. Bichi, S. Zupo, E. Noch, H. Aldler, S. Rattan, M. Keating, K. Rai, L. Rassenti, T. Kipps, M. Negrini, F. Bullrich and C. M. Croce (2002). "Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia." Proc Natl Acad Sci U S A 99(24): 15524-15529.

Cellini, L., L. Marzio, G. Ferrero, A. Del Vino, E. Di Campli, L. Grossi, S. Toracchio and L. Artese (2001). "Transmission of Helicobacter pylori in an animal model." Digestive diseases and sciences 46(1): 62-68.

Chan, S. H., C. W. Wu, A. F. Li, C. W. Chi and W. C. Lin (2008). "miR-21 microRNA expression in human gastric carcinomas and its clinical association." Anticancer Res 28(2A): 907-911.

Chen, C. Z., L. Li, H. F. Lodish and D. P. Bartel (2004). "MicroRNAs modulate hematopoietic lineage differentiation." Science 303(5654): 83-86.

Cheng, A. M., M. W. Byrom, J. Shelton and L. P. Ford (2005). "Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis." Nucleic Acids Research 33(4): 1290-1297.

Correa, P., J. Fox, E. Fontham, B. Ruiz, Y. P. Lin, D. Zavala, N. Taylor, D. Mackinley, E. de Lima, H. Portilla and et al. (1990). "Helicobacter pylori and gastric carcinoma. Serum antibody prevalence in populations with contrasting cancer risks." Cancer 66(12): 2569-2574.

Cover, T. L. and S. R. Blanke (2005). "Helicobacter pylori VacA, a paradigm for toxin multifunctionality." Nature Reviews Microbiology 3(4): 320-332.

Cowin, P. (1994). "Unraveling the cytoplasmic interactions of the cadherin superfamily." Proc Natl Acad Sci U S A 91(23): 10759.

Delluva, A., K. Markley and R. Davies (1968). "The absence of gastric urease in germ-free animals." Biochimica et Biophysica Acta (BBA)-Enzymology 151(3): 646-650.

Forman, D., D. Newell, F. Fullerton, J. Yarnell, A. Stacey, N. Wald and F. Sitas (1991). "Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation." BMJ: British Medical Journal 302(6788): 1302.

Franco, A. T., D. A. Israel, M. K. Washington, U. Krishna, J. G. Fox, A. B. Rogers, A. S. Neish, L. Collier-Hyams, G. I. Perez-Perez, M. Hatakeyama, R. Whitehead, K. Gaus, D. P. O'Brien, J. Romero-Gallo and R. M. Peek, Jr. (2005). "Activation of beta-catenin by carcinogenic Helicobacter pylori." Proc Natl Acad Sci U S A 102(30): 10646-10651.

Go, M. F. (1996). "Helicobacter pylori: its role in ulcer disease and gastric cancer and how to detect the infection." Acta Gastroenterologica Latinoamericana 26: 45-50.

Goodwin, C., R. McCulloch, J. Armstrong and S. Wee (1985). "Unusual cellular fatty acids and distinctive ultrastructure in a new spiral bacterium (Campylobacter pyloridis) from the human gastric mucosa." Journal of medical microbiology 19(2): 257-267.

Goodwin, C. S., J. A. Armstrong, T. Chilvers, M. Peters, M. D. Collins, L. SLY, W. McCONNELL and W. E. S. HARPER (1989). "Transfer of Campylobacter pylori and Campylobacter mustelae to Helicobacter gen. nov. as Helicobacter pylori comb. nov. and Helicobacter mustelae comb. nov., respectively." International journal of systematic bacteriology 39(4): 397-405.

Gregory, P. A., A. G. Bert, E. L. Paterson, S. C. Barry, A. Tsykin, G. Farshid, M. A. Vadas, Y. Khew-Goodall and G. J. Goodall (2008). "The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1." Nat Cell Biol 10(5): 593-601.

Guo, L. and Z. Lu (2010). "Expression analysis of microRNA cluster based on isomiRs from high throughput DNA sequencing data." Bioinformatics and Biomedical Technology (ICBBT), 2010 International Conference on: 195-197.

Hammond, S. M., S. Boettcher, A. A. Caudy, R. Kobayashi and G. J. Hannon (2001). "Argonaute2, a link between genetic and biochemical analyses of RNAi." Science Signalling 293(5532): 1146.

Hatakeyama, M. (2008). "SagA of CagA in Helicobacter pylori pathogenesis." Current opinion in microbiology 11(1): 30-37.

Hatakeyama, M. (2009). "Helicobacter pylori and gastric carcinogenesis." Journal of gastroenterology 44(4): 239-248.

He, H., K. Jazdzewski, W. Li, S. Liyanarachchi, R. Nagy, S. Volinia, G. A. Calin, C. G. Liu, K. Franssila, S. Suster, R. T. Kloos, C. M. Croce and A. de la Chapelle (2005). "The role of microRNA genes in papillary thyroid carcinoma." Proc Natl Acad Sci U S A 102(52): 19075-19080.

He, L. and G. J. Hannon (2004). "MicroRNAs: small RNAs with a big role in gene regulation." Nature Reviews Genetics 5(7): 522-531.

He, T. C., A. B. Sparks, C. Rago, H. Hermeking, L. Zawel, L. T. da Costa, P. J. Morin, B. Vogelstein and K. W. Kinzler (1998). "Identification of c-MYC as a target of the APC pathway." Science 281(5382): 1509-1512.

Hossain, A., M. T. Kuo and G. F. Saunders (2006). "Mir-17-5p regulates breast cancer cell proliferation by inhibiting translation of AIB1 mRNA." Mol Cell Biol 26(21): 8191-8201.

Huang, K., J. X. Zhang, L. Han, Y. P. You, T. Jiang, P. Y. Pu and C. S. Kang (2010). "MicroRNA roles in beta-catenin pathway." Mol Cancer 9(1): 252.

Huang, T.-J. and P. S. Li (2001). "Dexamethasone inhibits luteinizing hormone-induced synthesis of steroidogenic acute regulatory protein in cultured rat preovulatory follicles." Biology of Reproduction 64: 163-170.

Hulten, K., S. Han, H. Enroth, P. Klein, A. Opekun, R. Gilman, D. Evans, L. Engstrand, D. Graham and F. El-Zaatari (1996). "Helicobacter pylori in the drinking water in Peru." Gastroenterology 110(4): 1031-1035.

Hung, K. H., J. J. Wu, H. B. Yang, L. J. Su and B. S. Sheu (2009). "Host Wnt/beta-catenin pathway triggered by Helicobacter pylori correlates with regression of gastric intestinal metaplasia after H. pylori eradication." J Med Microbiol 58(Pt 5): 567-576.

Hwang, H. W., E. A. Wentzel and J. T. Mendell (2007). "A hexanucleotide element directs microRNA nuclear import." Science 315(5808): 97-100.

Iorio, M. V., M. Ferracin, C. G. Liu, A. Veronese, R. Spizzo, S. Sabbioni, E. Magri, M. Pedriali, M. Fabbri, M. Campiglio, S. Menard, J. P. Palazzo, A. Rosenberg, P. Musiani, S. Volinia, I. Nenci, G. A. Calin, P. Querzoli, M. Negrini and C. M. Croce (2005). "MicroRNA gene expression deregulation in human breast cancer." Cancer Res 65(16): 7065-7070.

Iorio, M. V., R. Visone, G. Di Leva, V. Donati, F. Petrocca, P. Casalini, C. Taccioli, S. Volinia, C. G. Liu, H. Alder, G. A. Calin, S. Menard and C. M. Croce (2007). "MicroRNA signatures in human ovarian cancer." Cancer Res 67(18): 8699-8707.

Israel, D. A., A. S. Lou and M. J. Blaser (2006). "Characteristics of Helicobacter pylori natural transformation." FEMS microbiology letters 186(2): 275-280.

Karp, X. and V. Ambros (2005). "Enhanced: Encountering MicroRNAs in Cell Fate Signaling." Science Signalling 310(5752): 1288.

Kersulyte, D., A. K. Mukhopadhyay, B. Velapatiño, W. W. Su, Z. J. Pan, C. Garcia, V. Hernandez, Y. Valdez, R. S. Mistry and R. H. Gilman (2000). "Differences in genotypes of Helicobacter pylori from different human populations." Journal of bacteriology 182(11): 3210-3218.

Khvorova, A., A. Reynolds and S. D. Jayasena (2003). "Functional siRNAs and miRNAs exhibit strand bias." Cell 115(2): 209-216.

Kim, K., Z. Lu and E. D. Hay (2002). "Direct evidence for a role of β-catenin/LEF-1 signaling pathway in induction of EMT." Cell biology international 26(5): 463-476.

Korpal, M. and Y. Kang (2008). "The emerging role of miR-200 family of microRNAs in epithelial-mesenchymal transition and cancer metastasis." RNA biology 5(3): 115-119.

Korpal, M., E. S. Lee, G. Hu and Y. Kang (2008). "The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2." J Biol Chem 283(22): 14910-14914.

Kozomara, A. and S. Griffiths-Jones (2011). "miRBase: integrating microRNA annotation and deep-sequencing data." Nucleic Acids Res. 39(Database issue): D152-157.

Kurashima, Y., N. Murata-Kamiya, K. Kikuchi, H. Higashi, T. Azuma, S. Kondo and M. Hatakeyama (2008). "Deregulation of beta-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence." Int J Cancer 122(4): 823-831.

Kutay, H., S. Bai, J. Datta, T. Motiwala, I. Pogribny, W. Frankel, S. T. Jacob and K. Ghoshal (2006). "Downregulation of miR-122 in the rodent and human hepatocellular carcinomas." J Cell Biochem 99(3): 671-678.

Lagos-Quintana, M., R. Rauhut, W. Lendeckel and T. Tuschl (2001). "Identification of novel genes coding for small expressed RNAs." Science Signalling 294(5543): 853.

LamondLab. (2012). "Nucleolar Isolation Protocol." http://www.lamondlab.com/f7nucleolarprotocol.htm.

Larsen, M., M. L. Tremblay and K. M. Yamada (2003). "Phosphatases in cell–matrix adhesion and migration." Nature Reviews Molecular Cell Biology 4(9): 700-711.

Lee, R. C. and V. Ambros (2001). "An extensive class of small RNAs in Caenorhabditis elegans." Science Signalling 294(5543): 862.

Lee, R. C., R. L. Feinbaum and V. Ambros (1993). "The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14." Cell 75(5): 843-854.

Lee, Y., C. Ahn, J. Han, H. Choi, J. Kim, J. Yim, J. Lee, P. Provost, O. Radmark and S. Kim (2003). "The nuclear RNase III Drosha initiates microRNA processing." Nature 425(6956): 415-419.

Lee, Y., M. Kim, J. Han, K. H. Yeom, S. Lee, S. H. Baek and V. N. Kim (2004). "MicroRNA genes are transcribed by RNA polymerase II." EMBO J 23(20): 4051-4060.

Lim, L. P., M. E. Glasner, S. Yekta, C. B. Burge and D. P. Bartel (2003). "Vertebrate microRNA genes." Science 299(5612): 1540-1540.

Lin, C., Y. Chang, S. Wu and K. Cheng (1998). "Helicobacter pylori in gastric biopsies of Taiwanese patients with gastroduodenal diseases." Japanese Journal of Medical Science and Biology 51: 13-23.

Lin, J. T., L. Y. Wang, J. T. Wang, T. H. Wang and C. J. Chen (1995). "Ecological study of association between Helicobacter pylori infection and gastric cancer in Taiwan." Digestive diseases and sciences 40(2): 385-388.

Livak, K. J. and T. D. Schmittgen (2001). "Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2 − ΔΔCT Method." Methods 25(4): 402-408.

Logan, C. Y. and R. Nusse (2004). "The Wnt signaling pathway in development and disease." Annu. Rev. Cell Dev. Biol. 20: 781-810.

Lui, W. O., N. Pourmand, B. K. Patterson and A. Fire (2007). "Patterns of known and novel small RNAs in human cervical cancer." Cancer Res 67(13): 6031-6043.

Mahdavi, J., B. Sondén, M. Hurtig, F. O. Olfat, L. Forsberg, N. Roche, J. Ångström, T. Larsson, S. Teneberg and K. A. Karlsson (2002). "Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation." Science 297(5581): 573-578.

Malaty, H. and D. Graham (1994). "Importance of childhood socioeconomic status on the current prevalence of Helicobacter pylori infection." Gut 35(6): 742-745.

Mann, B., M. Gelos, A. Siedow, M. Hanski, A. Gratchev, M. Ilyas, W. Bodmer, M. Moyer, E. Riecken and H. Buhr (1999). "Target genes of β-catenin–T cell-factor/lymphoid-enhancer-factor signaling in human colorectal carcinomas." Proceedings of the National Academy of Sciences 96(4): 1603-1608.

Marshall, B. (2002). "Helicobacter pylori: 20 years on." Clin Med 2(2): 147-152.

Marshall, B. J., C. S. Goodwin, J. R. Warren, R. Murray, E. D. Blincow, S. J. Blackbourn, M. Phillips, T. E. Waters and C. R. Sanderson (1988). "Prospective double-blind trial of duodenal ulcer relapse after eradication of Campylobacter pylori." Lancet 2(8626-8627): 1437-1442.

Marshall, B. J. and J. R. Warren (1984). "Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration." The Lancet 323(8390): 1311-1315.

Matsushima, K., H. Isomoto, N. Inoue, T. Nakayama, T. Hayashi, M. Nakayama, K. Nakao, T. Hirayama and S. Kohno (2011). "MicroRNA signatures in Helicobacter pylori-infected gastric mucosa." Int J Cancer 128(2): 361-370.

Melo, S. A., C. Moutinho, S. Ropero, G. A. Calin, S. Rossi, R. Spizzo, A. F. Fernandez, V. Davalos, A. Villanueva, G. Montoya, H. Yamamoto, S. Schwartz, Jr. and M. Esteller (2010). "A genetic defect in exportin-5 traps precursor microRNAs in the nucleus of cancer cells." Cancer Cell 18(4): 303-315.

Meng, F., R. Henson, H. Wehbe-Janek, K. Ghoshal, S. T. Jacob and T. Patel (2007). "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer." Gastroenterology 133(2): 647.

Meng, F., R. Henson, H. Wehbe-Janek, K. Ghoshal, S. T. Jacob and T. Patel (2007). "MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer." Gastroenterology 133(2): 647-658.

Mongroo, P. S. and A. K. Rustgi (2010). "The role of the miR-200 family in epithelial-mesenchymal transition." Cancer Biology & Therapy 10(3): 219-222.

Moon, R. T., A. D. Kohn, G. V. De Ferrari and A. Kaykas (2004). "WNT and beta-catenin signalling: diseases and therapies." Nat Rev Genet 5(9): 691-701.

Morin, P. J., A. B. Sparks, V. Korinek, N. Barker, H. Clevers, B. Vogelstein and K. W. Kinzler (1997). "Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC." Science 275(5307): 1787-1790.

Murata-Kamiya, N., Y. Kurashima, Y. Teishikata, Y. Yamahashi, Y. Saito, H. Higashi, H. Aburatani, T. Akiyama, R. M. Peek, Jr., T. Azuma and M. Hatakeyama (2007). "Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells." Oncogene 26(32): 4617-4626.

Nagafuchi, A. and M. Takeichi (1989). "Transmembrane control of cadherin-mediated cell adhesion: a 94 kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin." Cell regulation 1(1): 37.

Nakayama, M., J. Hisatsune, E. Yamasaki, H. Isomoto, H. Kurazono, M. Hatakeyama, T. Azuma, Y. Yamaoka, K. Yahiro, J. Moss and T. Hirayama (2009). "Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway." J Biol Chem 284(3): 1612-1619.

Pakodi, F., O. M. E. Abdel-Salam, A. Debreceni and G. Mózsik (2000). "Helicobacter pylori. One bacterium and a broad spectrum of human disease! An overview." Journal of Physiology-Paris 94(2): 139-152.

Pallante, P., R. Visone, M. Ferracin, A. Ferraro, M. T. Berlingieri, G. Troncone, G. Chiappetta, C. G. Liu, M. Santoro, M. Negrini, C. M. Croce and A. Fusco (2006). "MicroRNA deregulation in human thyroid papillary carcinomas." Endocr Relat Cancer 13(2): 497-508.

Pan, Z. J., R. Van der Hulst, M. Feller, S. D. Xiao, G. Tytgat, J. Dankert and A. Van Der Ende (1997). "Equally high prevalences of infection with cagA-positive Helicobacter pylori in Chinese patients with peptic ulcer disease and those with chronic gastritis-associated dyspepsia." Journal of clinical microbiology 35(6): 1344-1347.

Parsonnet, J., G. D. Friedman, D. P. Vandersteen, Y. Chang, J. H. Vogelman, N. Orentreich and R. K. Sibley (1991). "Helicobacter pylori infection and the risk of gastric carcinoma." New England Journal of Medicine 325(16): 1127-1131.

Parsonnet, J., S. Hansen, L. Rodriguez, A. B. Gelb, R. A. Warnke, E. Jellum, N. Orentreich, J. H. Vogelman and G. D. Friedman (1994). "Helicobacter pylori infection and gastric lymphoma." New England Journal of Medicine 330(18): 1267-1271.

Pasquinelli, A. E., B. J. Reinhart, F. Slack, M. Q. Martindale, M. I. Kuroda, B. Maller, D. C. Hayward, E. E. Ball, B. Degnan and P. Muller (2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA." Nature: 86-88.

Peck, B., M. Ortkamp, K. D. Diehl, E. Hundt and B. Knapp (1999). "Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori." Nucleic Acids Research 27(16): 3325-3333.

Peifer, M. and P. Polakis (2000). "Wnt signaling in oncogenesis and embryogenesis--a look outside the nucleus." Science 287(5458): 1606-1609.

Poy, M. N., L. Eliasson, J. Krutzfeldt, S. Kuwajima, X. Ma, P. E. MacDonald, S. Pfeffer, T. Tuschl, N. Rajewsky and P. Rorsman (2004). "A pancreatic islet-specific microRNA regulates insulin secretion." Nature 432(7014): 226-230.

Price, A. B. (1999). "Classification of gastritis--yesterday, today and tomorrow." Verhandlungen der Deutschen Gesellschaft für Pathologie 83: 52.

Prinz, C., M. Schöniger, R. Rad, I. Becker, E. Keiditsch, S. Wagenpfeil, M. Classen, T. Rösch, W. Schepp and M. Gerhard (2001). "Key importance of the Helicobacter pylori adherence factor blood group antigen binding adhesin during chronic gastric inflammation." Cancer Res 61(5): 1903-1909.

Roldo, C., E. Missiaglia, J. P. Hagan, M. Falconi, P. Capelli, S. Bersani, G. A. Calin, S. Volinia, C. G. Liu, A. Scarpa and C. M. Croce (2006). "MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior." J Clin Oncol 24(29): 4677-4684.

Romaniuk, P. J., B. Zoltowska, T. J. Trust, D. J. Lane, G. Olsen, N. Pace and D. Stahl (1987). "Campylobacter pylori, the spiral bacterium associated with human gastritis, is not a true Campylobacter sp." Journal of bacteriology 169(5): 2137-2141.

Romano, M., V. Ricci and R. Zarrilli (2006). "Mechanisms of Disease: Helicobacter pylori-related gastric carcinogenesis—implications for chemoprevention." Nature Clinical Practice Gastroenterology & Hepatology 3(11): 622-632.

Saydam, O., Y. Shen, T. Wurdinger, O. Senol, E. Boke, M. F. James, B. A. Tannous, A. O. Stemmer-Rachamimov, M. Yi, R. M. Stephens, C. Fraefel, J. F. Gusella, A. M. Krichevsky and X. O. Breakefield (2009). "Downregulated microRNA-200a in meningiomas promotes tumor growth by reducing E-cadherin and activating the Wnt/beta-catenin signaling pathway." Mol Cell Biol 29(21): 5923-5940.

Sewald, X., W. Fischer and R. Haas (2008). "Sticky socks: Helicobacter pylori VacA takes shape." Trends in microbiology 16(3): 89-92.

Sheu, S. M., B. S. Sheu, H. B. Yang, C. Li, T. C. Chu and J. J. Wu (2002). "Presence of iceA1 but not cagA, cagC, cagE, cagF, cagN, cagT, or orf13 genes of Helicobacter pylori is associated with more severe gastric inflammation in Taiwanese." Journal of the Formosan Medical Association= Taiwan yi zhi 101(1): 18.

Sokolova, O., P. M. Bozko and M. Naumann (2008). "Helicobacter pylori suppresses glycogen synthase kinase 3beta to promote beta-catenin activity." J Biol Chem 283(43): 29367-29374.

Sotiropoulou, G., G. Pampalakis, E. Lianidou and Z. Mourelatos (2009). "Emerging roles of microRNAs as molecular switches in the integrated circuit of the cancer cell." RNA 15(8): 1443-1461.

Staal, F. J. T., M. van Noort, G. J. Strous and H. C. Clevers (2002). "Wnt signals are transmitted through N-terminally dephosphorylated β-catenin." EMBO Rep 3(1): 63-68.

Suerbaum, S. and P. Michetti (2002). "Helicobacter pylori infection." New England Journal of Medicine 347(15): 1175-1186.

Supajatura, V., H. Ushio, A. Wada, K. Yahiro, K. Okumura, H. Ogawa, T. Hirayama and C. Ra (2002). "Cutting edge: VacA, a vacuolating cytotoxin of Helicobacter pylori, directly activates mast cells for migration and production of proinflammatory cytokines." The Journal of Immunology 168(6): 2603-2607.

Tabassam, F. H., D. Y. Graham and Y. Yamaoka (2008). "Helicobacter pylori activate epidermal growth factor receptor-and phosphatidylinositol 3-OH kinase-dependent Akt and glycogen synthase kinase 3β phosphorylation." Cellular microbiology 11(1): 70-82.

Teh, B., J. Lin, W. Pan, S. Lin, L. Y. Wang, T. Lee and C. Chen (1994). "Seroprevalence and associated risk factors of Helicobacter pylori infection in Taiwan." Anticancer research 14(3B): 1389.

Tetsu, O. and F. McCormick (1999). "β-Catenin regulates expression of cyclin D1 in colon carcinoma cells." Nature 398(6726): 422-426.

Van Doorn, L. J., C. Figueiredo, F. Megraud, S. Pena, P. Midolo, D. M. Queiroz, F. Carneiro, B. Vanderborght, M. D. Pegado, R. Sanna, W. De Boer, P. M. Schneeberger, P. Correa, E. K. Ng, J. Atherton, M. J. Blaser and W. G. Quint (1999). "Geographic distribution of vacA allelic types of Helicobacter pylori." Gastroenterology 116(4): 823-830.

Viswanathan, S. R., C. H. Mermel, J. Lu, C. W. Lu, T. R. Golub and G. Q. Daley (2009). "microRNA expression during trophectoderm specification." PloS one 4(7): e6143.

Wen, S. and S. F. Moss (2009). "Helicobacter pylori virulence factors in gastric carcinogenesis." Cancer Letters 282(1): 1-8.

Wightman, B., I. Ha and G. Ruvkun (1993). "Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans." Cell 75(5): 855-862.

Winter, J., S. Jung, S. Keller, R. I. Gregory and S. Diederichs (2009). "Many roads to maturity: microRNA biogenesis pathways and their regulation." Nat Cell Biol 11(3): 228-234.

Wong, B. C. Y., Y. Yin, D. E. Berg, H. H. X. Xia, J. Z. Zhang, W. H. Wang, W. M. Wong, X. R. Huang, V. S. Y. Tang and S. K. Lam (2002). "Distribution of distinct vacA, cagA and iceA alleles in Helicobacter pylori in Hong Kong." Helicobacter 6(4): 317-324.

Wotherspoon, A. (1998). "Helicobacter pylori infection and gastric lymphoma." British medical bulletin 54(1): 79-85.

Wu, L., J. Fan and J. G. Belasco (2006). "MicroRNAs direct rapid deadenylation of mRNA." Proc Natl Acad Sci U S A 103(11): 4034-4039.

Xia, H., W. K. Cheung, J. Sze, G. Lu, S. Jiang, H. Yao, X. W. Bian, W. S. Poon, H. F. Kung and M. C. Lin (2010). "miR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and beta-catenin signaling." J Biol Chem 285(47): 36995-37004.

Xia, H., L. L. P. J. Ooi and K. M. Hui (2012). "MiR-214 Targets β-Catenin Pathway to Suppress Invasion, Stem-Like Traits and Recurrence of Human Hepatocellular Carcinoma." PloS one 7(9): e44206.

Xu, P., M. Guo and B. A. Hay (2004). "MicroRNAs and the regulation of cell death." TRENDS in Genetics 20(12): 617-624.

Yamaguchi, H., T. Osaki, N. Kurihara, H. Taguchi, T. Hanawa, T. Yamamoto and S. Kamiya (1997). "Heat-shock protein 60 homologue of Helicobacter pylori is associated with adhesion of H. pylori to human gastric epithelial cells." Journal of medical microbiology 46(10): 825-831.

Yang, J. S., M. D. Phillips, D. Betel, P. Mu, A. Ventura, A. C. Siepel, K. C. Chen and E. C. Lai (2011). "Widespread regulatory activity of vertebrate microRNA* species." RNA 17(2): 312-326.

Ying, S. Y. and S. L. Lin (2005). "Intronic microRNAs." Biochem Biophys Res Commun 326(3): 515-520.

Yu, J., F. Wang, G. H. Yang, F. L. Wang, Y. N. Ma, Z. W. Du and J. W. Zhang (2006). "Human microRNA clusters: genomic organization and expression profile in leukemia cell lines." Biochem Biophys Res Commun 349(1): 59-68.

Zeng, Y. and B. R. Cullen (2004). "Structural requirements for pre-microRNA binding and nuclear export by Exportin 5." Nucleic Acids Research 32(16): 4776-4785.

Zhang, W., J. E. Dahlberg and W. Tam (2007). "MicroRNAs in tumorigenesis: a primer." The American journal of pathology 171(3): 728-738.

Zhang, Z., Z. Li, C. Gao, P. Chen, J. Chen, W. Liu, S. Xiao and H. Lu (2008). "miR-21 plays a pivotal role in gastric cancer pathogenesis and progression." Lab Invest 88(12): 1358-1366.

洪偉珉 (2012). A novel transcriptional repressor complex composed of KLF12/hKID3 involved in surface gene deregulation in a hepatocellular carcinoma-inducing hepatitis B virus preS mutant, 國立成功大學微生物及免疫學研究所碩士論文.
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