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研究生:林耑妤
研究生(外文):Lin, Jhuan-Yu
論文名稱:葉酸缺乏調節後基因甲基化作用啟動Hedgehog傳訊機制促進結腸癌細胞侵犯性
論文名稱(外文):Folate Deficiency Promotes Invasion of Colon Adenocarcinoma Cells Through Epigenetic Regulation On Aberrant Activation of Hedgehog Signaling Pathway
指導教授:許瑞芬許瑞芬引用關係
指導教授(外文):Rwei-Fen S. Huang
口試委員:魏耀揮林蔚靖
口試委員(外文):Wei, Yao-HuiLin, Wey-Jinq
口試日期:2011.07.16
學位類別:碩士
校院名稱:輔仁大學
系所名稱:營養科學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2011
畢業學年度:99
語文別:中文
論文頁數:111
中文關鍵詞:葉酸結腸癌Hedgehog訊息傳遞甲基化轉移
外文關鍵詞:folate deficiencycolorectal cancerHedgehog signalingmethylationmetastasis
相關次數:
  • 被引用被引用:2
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  • 下載下載:11
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流行病學研究指出低葉酸營養狀態增加罹患結腸癌風險性。葉酸缺乏是否促進結腸癌細胞進階發展侵犯性國內外尚無相關文獻報導。Hedgehog (Hh)訊息傳遞參與胚胎期腸胃道發育分化,活化Hh訊息傳遞被認為是主導腸道腫瘤進階轉移發展的關鍵調控。啟動Hh訊息傳遞的原因未明,可能與傳訊分子sonic hedgehog(Shh)啟動子甲基化相關。本研究探討葉酸缺乏是否藉由調節Hh傳訊配體Shh啟動子甲基化,活化Hh傳訊並促進結腸癌細胞侵犯性。為模擬人類結腸癌細胞內變異分子傳遞情境及癌化階段,選用低侵犯性具Wnt訊息傳遞因子APC突變之結腸腺瘤細胞SW480為研究模式。實驗設計包含對照組、葉酸缺乏組及去甲基組(5-AZA),首先分析有無透析血清葉酸中之細胞內葉酸含量,結果顯示,相較於對照組,葉酸缺乏72小時其細胞內葉酸含量顯著降低,無/有透析葉酸缺乏組為分別為54.70μg/ml及 50.45μg/ml,而無/有透析對照組則分別為147.04μg/ml 及146.01μg/ml,顯示有無透析血清葉酸對細胞內葉酸濃度無影響。另外發現,相較對照組,葉酸缺乏顯著增加SW480細胞侵犯性5.5倍及黏著性1.53倍(P <0.05),加入5-AZA亦分別促進對照組與葉酸缺乏組之侵犯性1.9及1.87倍;以即時定量PCR分析及西方點墨法分析Shh分子表現,發現葉酸缺乏組的Shh基因及蛋白質表現顯著增加1.72及1.67倍,以5-AZA處理可顯著增加其Shh基因表現2.08倍及蛋白質表現2.26倍;且葉酸缺乏與5-AZA處理同時顯著上調Hh傳訊路徑中的Hh配體(Ihh)、二級傳訊分子(Smo)、轉錄因子(Gli1)及下游標的促轉移基因(Snail、MMP-2),降低β-catenin及表皮細胞標記(E-cadherin)基因表現,顯示葉酸缺乏與去甲基作用分別活化Hh傳訊分子基因表現並調控EMT (epithelial-mesenchymal transition)的基因表現型態。以重亞硫酸鹽(bisulfite)處理,並設計甲基特異性PCR(MSP)引子分析Shh基因啟動子甲基化狀態,結果顯示,對照組為Shh基因啟動子甲基化,而葉酸缺乏及5-AZA處理則促進SW480細胞中Shh基因啟動子去甲基化。當投予Hh傳訊抑制劑cyclopamine可顯著抑制葉酸缺乏及去甲基所啟動的Shh基因調控與蛋白質表現,降低Hh傳訊分子表現,反轉EMT的基因調控,降低MMPs (matrix metalloproteinases)的活性,消除SW480的侵犯性。綜合研究結果,葉酸缺乏經由降低Shh啟動子甲基化狀態,促進Shh與Hh傳訊分子基因表現,啟動轉移相關標地分子表現,促進結腸癌細胞SW480的侵犯性。
中文摘要 I
英文摘要 III
致謝 V
目錄 VII
圖目錄 X
縮寫表 XI
第一章 前言 1
第二章 文獻回顧 3
一、結腸癌簡介 3
(一)結腸癌之風險因子 3
(二)結腸癌的形成及治療 3
二、癌細胞侵犯轉移之機制 5
(一)表皮-間葉轉換系統(epithelial-mesenchymal transition,EMT ) 5
(二)間質金屬蛋白酶(matrix metalloproteinases, MMPs)在結腸癌轉移扮演之角色 7
三、啟動侵犯轉移之分子機制 9
(一) Hedgehog (Hh)訊息傳遞路徑 9
1. Hh傳訊途徑之分子機制(詳見圖一) 9
2. Hh傳訊途徑與癌細胞之侵犯轉移性 10
3. Hedgehog訊息傳遞路徑與EMT 13
(二) Wnt/β-catenin訊息傳遞路徑 14
1. Wnt傳訊路徑之分子機制 14
2. Wnt傳訊路徑與癌細胞之侵犯轉移性 14
(三) NF-κB訊息傳遞 16
1. NF-κB訊息傳遞之分子機制 16
2. NF-κB與大腸直腸癌之侵犯及轉移性 16
四、Hh傳訊途徑與轉移相關傳訊途徑之交互作用 18
(一) NF-κB與Hh訊息傳遞路徑之相關性 18
(二) Hh傳訊途徑與Wnt傳訊途徑之交互作用 20
五、葉酸營養狀態與結腸癌 21
(一) 葉酸營養狀態與罹患結腸癌之風險相關性 21
(二) 葉酸營養狀態與結腸癌轉移侵犯之關係 23
(三) 葉酸營養狀態與甲基化 24
1. DNA甲基化 24
2. Hh訊息傳遞分子之甲基化 25
(1) Shh基因啟動子甲基化 25
(2) HHIP基因啟動子甲基化 26
(3) Smo基因啟動子甲基化 27
六、研究目的 28
第三章 實驗材料與方法 29
一、實驗設計 29
二、實驗材料 31
(一) 細胞株 31
(二) 實驗用試藥 31
(三) 培養基 32
(四) 實驗設備(詳見附表三) 33
三、實驗方法及分析項目 34
(一) 細胞培養 34
(二) 藥劑配置 34
(三) 葉酸含量分析( L. Casei assay) 35
(四) 黏著能力分析( adhesion assay ) 35
(五) 侵犯能力分析( invasion assay ) 36
(六) 明膠酶譜法(zymography) 37
(七) 西方墨點法( Western blot ) 38
(八) 反轉錄聚合酶連鎖反應(Reverse transcription-PCR) 40
(九) 及時定量聚合酶連鎖反應(Real-time PCR) 42
(十) 甲基特異性PCR (MSP) 43
四、統計分析 46
第四章 結果 47
一、 葉酸缺乏或去甲基(5-aza-dCyd)促進結腸癌細胞SW480之侵犯性 47
二、 葉酸缺乏與去甲基經由Hedgehog訊息傳遞路徑誘發結腸腺癌侵犯性 47
三、 葉酸缺乏與去甲基(5-aza-dCyd)對Hh傳訊及下游侵犯相關分子之影響 48
四、 葉酸缺乏與去甲基(5-aza-dCyd)增加間質金屬蛋白酶(MMPs)活性 49
五、 葉酸缺乏與去甲基(5-aza-dCyd)調節Hh傳訊配體(Shh)基因甲基化 49
第五章 討論 51
一、葉酸缺乏或去甲基(5-aza-dCyd)促進結腸腺瘤細胞SW480之侵犯性 51
二、葉酸缺乏或去甲基(5-aza-dCyd) 經由Hedgehog訊息傳遞路徑誘發結腸腺癌侵犯性 52
三、葉酸缺乏與去甲基(5-aza-dCyd)經由Hh傳訊調控下游侵犯轉移相關分子 56
四、葉酸缺乏與去甲基(5-aza-dCyd)經由調控Hh傳訊配體(Shh)基因甲基化而促進結腸癌細胞轉移 59
第六章 總結 63
圖表 65
參考文獻 77
附表及附圖 90

參考文獻
行政院衛生署國民健康局

王姿萍 (2010) 葉酸不足與葉酸拮抗劑methotrexate處理活化轉錄因子NF-κB調控Hedgehog訊息傳遞促進人類結腸癌細胞表現體外轉移。私立輔仁大學營養科學系碩士論文。

林振豪 (2008) 葉酸缺乏調節肝癌細胞株移動與侵襲性及其相關訊息傳遞分子基因表現。私立輔仁大學營養科學系碩士論文。

邱文駿 (2009) 葉酸營養與發炎反應調節肝癌細胞移動和侵犯性及作用訊息傳遞分子機制。私立輔仁大學營養科學系碩士論文。

Akiyoshi T, Nakamura M, Koga K, Nakashima H, Yao T, Tsuneyoshi M, Tanaka M, Katano M. Gli1, downregulated in colorectal cancers, inhibits proliferation of colon cancer cells involving Wnt signalling activation. Gut. 2006;55:991-9.

Albini A and Sporn MB. The tumor microenvironment as a target for chemoprevention. Nat Rev Cancer. 2007;7:139-47.

Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, Hoek KS, Juàrez P, Goydos JS, Fournier PJ, Sibon C, Bertolotto C, Verrecchia F, Saule S, Delmas V, Ballotti R, Larue L, Saiag P, Guise TA, Mauviel A. GLI2-mediated melanoma invasion and metastasis. J Natl Cancer Inst. 2010;15:1148-59.

Arias AM. Epithelial mesencymal interactions in cancer and development. Cell. 2001;105:425-31.
Arimura S, Matsunaga A, Kitamura T, Aoki K, Aoki M, Taketo MM. Reduced level of smoothened suppresses intestinal tumorigenesis by down-regulation of Wnt signaling. Gastroenterology. 2009;137:629-38.

Bailey LB, Rampersaud GC, Kauwell GP. Folic acid supplements and fortification affect the risk for neural tube defects, vascular disease and cancer: evolving science. J Nutr. 2003;133:1961-8.

Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, Garcia De Herreros A. The transcription factor snail is a recrptor of E-cadherin gene expression in epithelial tumor cell. Nat Cell Biol. 2000;2:84-9.

Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432:324-31.

Benyon RC, Arthur MJ. Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis. 2001;21:373-84.

Berman DM, Karhadkar SS, Maitra A. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumors. Nature. 2003;425:846-51.

Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, PortilloF, Nieto MA. The transcription factor snail controls the epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2:76-83.

Calvert PM and Frucht H. The genetics of colorectal cancer. Ann Intern Med. 2002;137:603-12.

Cartwright C. Intestinal cell growth control: role of Src tyrosine kinases. Gastroenterology. 1998;114:1335-8.

Chatel G, Ganeff C, Boussif N. Hedgehog signaling pathway is inactive in colorectal cancer cell lines. Int J Cancer . 2007;121:2622-7.

Chen F, Castranova V, Shi XL. New insights into the role of nuclear factor-κB in cell growth regulation. Am J Pathol. 2001;159:387-97.

Choi SW, Mason JB. Folate status : effects on pathways of colorectal carcinogenesis. J Nutr. 2002;132:2413-8.

Cohen MM, Jr. The hedgehog signaling network. Am J Med Genet A. 2003;123A:5-28.

Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinases inhibitors and cancer: trials and tribulations. Science. 2002;295:2387-92.

Crawford, H.C., Matrisian, L.M. Mechanisms controlling the transcription of matrix metalloproteinase genes in normal and neoplastic cells. Enzyme Protein. 1996;49:20-37.

Crott JW, Liu Z, Keyes MK, Choi SW, Jang H, Moyer MP, Mason JB. Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines. J Nutr Biochem. 2008;19:328-35.

Davis CD, Uthus EO. DNA methylation, cancer susceptibility, and nutrient interaction. Exp Biol Med. 2004;229:988-95.

Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S. Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery. 2006;139:665-70.

Eaden JA, Mayberry JF. Colorectal cancer complicating ulcerative colitis: A review. Am J Gastroenterol. 2000;95:2710-9.

Egeblad M, Werb Z. New functions for matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161-74.

Fearnhead NS, Britton BP, Bodmer WF. The ABC of APC. Hum Mol Genet. 2001;10:721-33.

Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M, Karikari C, Alvarez H, Iacobuzio-Donahue C, Jimeno A, L. Gabrielson K, Matsui W, Maitra A. Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers. Cancer Res. 2007;67:2187-96.

Frosst, P., Blom, H. J., Milos, R., Goyette, P., et al., A candi-date genetic risk factor for vascular disease: A commonmutation in methylenetetrahydrofolate reductase. Nat Genet. 1995;10:111-3.

Gregorieff A and Clevers H. Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev. 2005;19:877-90.

Guarino M. Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 2007;39:2153-60.

Gupta GP, Nguyen DX, Chiang AC, Bos PD, Kim JY, Nadal C, Gomis RR, Manova-Todorova K, Massagué J. Nature. 2007;446:765-70.
Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC. Multivitamin use, folate, and colon cancer in women in the Nurses' Health Study. Ann Intern Med. 1998;129:517-24.

Hirohashi S. Inactivation of E-cadherin-mediated cell adhesion system in human cancer. Am J Pathol. 1998;153:333-9.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

Hamilton SR. The molecular genetics of colorectal neoplasia. Gastroenterology . 1993;105:3-7.

Hayashi I, Sohn KJ, Stempak JM, Croxford R, Kim YI. Folate Deficiency Induces Cell-Specific Changes in the Steady-State Transcript Levels of Genes Involved in Folate Metabolism and 1-Carbon Transfer Reactions in Human Colonic Epithelial Cells. J Nutr. 2007;137:607-13.

He J, Sheng T, Stelter AA, Li C, Zhang X, Sinha M, Luxon BA and Xie J. Suppressing Wnt Signaling by the Hedgehog Pathway through sFRP-1. Biol Chem. 2006;281:35598-602.

Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548-58.

Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ. Blockage of NF-kB activity in human prostate cancer cells is associate with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188-97.

Jacbo BP, Salky B. Laparoscopic colectomy for colon adenocarcinoma : an 11-year retrospective review with 5 survival rates. Surg Endosc. 2005;19:643-9.

Moscat J, Diaz-Meco MT, Rennert P. NF-κB activation by protein kinase C isoforms and B-cell function. EMBO Rep. 2003;4:31-6.

Kasperczyk H, Baumann B, Debatin KM, Fulda S. Characterization of sonic hedgehog as a novel NF-kappa B target gene that promotes NF-kappa B-mediated apoptosis resistance and tomor growth in vivo. FASEB J. 2009;23:21-33.

Kim YI, Fawaz K, Knox T, Lee YM. Colonic mucosal concentrations of folate correlate well with blood measurements of folate status in persons with colorectal polyps. Am J Clin Nutr. 1998;68:866-72.

Kim YI, Fawaz K, Knox T, Lee YM, Norton R, Libby E, Mason JB. Colonicmucosal concentrations of folate are accurately predicted by blood measurements of folate status among individuals ingesting physiologic quantities of folate. Cancer Epidemiol Biomarkers Prev. 2001;10:715-9.

Kim YI . Folate and colorectal cancer: an evidence-based critical review. Mol Nutr Food Res. 2007;51:267-92.

Kinzler KW, Vogelstein B. Lessons from hereditary colorectal cancer. Cell. 1996;87:159-70.

Kinzler KW, Bigner SH, Bigner DD, Trent JM, Law ML, O'Brien SJ, Wong AJ, Vogelstein B. Identification of an amplified, highly expressed gene in a human glioma. Science. 1987;236:70-3.

Lashner BA. Red blood cell folate is associated with the development of dysplasia and cancer in ulcerative colitis. J Cancer Res Clin Oncol. 1993;119:549-54.

Leyland H, Gentry J, Arthur MJ, Benyon RC. The plasminogen-activating system in hepatic stellate cells. Hepatology. 1996;24:1172-8.

Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP, Ngan HY, Cheung AN. Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis. 2009;30:131-40.

Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781-810.

Lukaszewicz-Zajac M, Mroczko B, Szmitkowski M. [The significance of metalloproteinases and their inhibitors in gastric cancer]. Postepy Hig Med Dosw (Online). 2009;63:258-65.

Ma X, Chen K, Huang S. Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis . 2005;26:1698-705.

MacMahon AP, Ingham PW, Tabin CJ. Developmental roles and clinical significance of hedgehog signaling. Curr Top Dev Biol. 2003;53:111-4.

Manthey CL, Vogel SN. The role of cytokines in host reponses to endotoxin. Rev Med Microbiol. 1992;3:72-9.

McCawley LJ, Matrisian LM. Matrix metalloproteinases: multifunctional contributors to tumor progression. Mol Med Today. 2000;6:149-56.

May MJ, Ghosh S. Rel/NF-κB and IκB proteins: an overview. Semin Cancer Biol. 1997;8:63-73.

May MJ, Ghosh S. Signal transducion through NF-κB. Immunol Today. 1998;19:80-8.

Missiaglia E, Donadelli M, Palmieri M, Crnogorac-Jurcevic T, Scarpa A, Lemoine NR. Growth delay of human pancreatic cancer cells by methylase inhibitor5-aza-2-deoxycytidine treatment is associated with activation of the interferon signalling pathway. Oncogene.2005;24:199-211.

Mtinx SR, Abe T, Maitra A, Goggins M. Aberrant methylation of the human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biol Ther. 2005;4:728-33.

Nakashima H, Nakamura M, Yamaguchi N, Akiyoshi T, Koga K, Yamaguchi K, Tsuneyoshi M, T anaka M, Katano M. Nuclear factor-kB contributes to hedgehoh signaling pathway activation through sonic hedgehog induction in pancreatic cancer. Cancer Res. 2006;66:7041-9.

Nagai S, Nakamura M, Yanai K, Wada J, Akiyoshi T, Nakashima H, Ohuchida K, Sato N, Tanaka M, Katano M. Gli1 contributes to invasiveness of pancreatic cancer through matrix metalloproteinase-9 activation. Cancer Sci. 2008;99:1377-84.

Narayan S, Roy D. Role of APC and DNA mismatch repair genes in the development of colorectal cancers. Mol Cancer. 2003;2:41-9.

Noel A, Emonard H, Polette M, Birembaut PH, Foidart JM. Role of matrix, fibroblast and type Ⅳ collagenases in tumur progression and invasion. Pathol Res Pract. 1994;190:934-41.

Novakovic P, M.Stempak J, Sohn KJ, Kim YI. Effects of folate deficiency on gene expression in the apoptosis and cancer pathways in colon cancer cells. Carcinogenesis. 2006;27;916-24.

Olsen CL, Hsu PP, Glienke J, Rubanyi GM, Brooks AR. Hedgehog-interacting protein is highly expressed in endothelial cells, but down-regulated during angiogenesis and in several human tumors. BMC Cancer. 2004;4:43-9.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.

Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer. 2003;3:903-11.

Paspatis GA and Karamanolis DG. Folate supplementation and adenomatous colonic polyps. Dis Colon Rectum. 1994;37:1340-1.

Prasanna P, Shack S, Wilson VL, Samid D. Phenylacetate in Chemoprevention : In Vitro and in Vivo Suppression of 5-Aza-2- Deoxycytidine-induced Carcinogenesis. Clin Cancer Res. 1995;1:865-71.

Price MA. CKI, there's more than one: casein kinase I family members in Wnt and Hedgehog signaling. Genes Dev. 2006;20:399-410.

Qualtrough D, Buda A, Gaffield W, Williams AC, Paraskeva C. Hedgehog signaling in colorectal tumor cells: induction of apoptosis with cyclopamine treatment. Int J Cancer. 2004;110:831-7.

Ruiz i Altaba A, Sanchez P, Dahmane N. Gli and hedgehog in cancer: tumours, embryos and stem cells. Nat Rev Cancer. 2002;2:361-72.

Sato N, Maehara N, Su GH, Goggins M. Effects of 5-Aza-2-deoxycytidine on Matrix Metalloproteinase Expression and Pancreatic Cancer Cell invasiveness. J Natl Cancer Inst. 2003;95:327-30.

Simiantonaki N, Kurzik-Dumke U, Karyofylli G, Jayasinghe C, Kirkpatatrick CJ. Loss of E-cadherin in the vanity of necrosis in colorectal carcinomas: association with NF-kB expression. Int J Oncol. 2007;31:269-75.

Simmonds RE, Foxwell BM. Signalling, inflammation and arthritis: NF-kappaB and its relevance to arthritis and inflammation. Rheumatology (Oxford). 2008;47:584-90.

Stepan V, Ramamoorthy S, Nitsche H, Zavros Y, Merchant JL, Todisco A. Regulation and function of the sonic hedgehog signal transduction pathway in isolated gastric parietal cells. J Biol Chem. 2005;280:15700-8.

Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr. 2006;83:895-904.

Silverman N, Maniatis T. NF-kappaB signaling pathways in mammalian and insect innate immunity. Genes Dev. 2001;15:2321-42.

Samowitz WS, Powers MD, Spirio LN, Nollet F, van Roy F, Slattery ML. Beta-catenin mutations are more frequent in small colorectal adenomas than in larger adenomas and invasive carcinomas. Cancer Res. 1999;59:1442-4.

Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M, Asaoka Y, Seto M, Muroyama R, Fukai K, Imazeki F, Kawabe T, Yokosuka O, Omata M. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res. 2008;14:3768-76.

Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000;407:530-5.

Taniguchi K, Roberts LR, Aderca IN, Dong X, Qian C, Murphy LM, Nagorney DM, Burgart LJ, Roche PC, Smith DI, Ross JA, Liu W. Mutational spectru of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21:4863-71.

Taniguchi H, Yamamoto H, Akutsu N, Nosho K, Adachi Y, Imai K, Shinomura Y. Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. J Pathol. 2007;213:131-9.

Tol J, Koopman M, Cats A, Rodenburg CJ, Creemers GJ, Schrama JG, Erdkamp FL, Vos AH, van Groeningen CJ, Sinnige HA. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med. 2009;360:563-72.

Tortola S, Marcuello E, Gonzalez I, Reyes G, Arribas R, Aiza G, Sancho FJ, Peinado MA, Capella G. p53 and K-ras gene mutations correlate with tumor aggressiveness but are not of routine prognostic value in colorectal cancer. J Clin Oncol. 1999;17:1375-81.

Van den Brink GR, Bleuming SA, Hardwick JC. Indian hedgehog is an antagonist of wnt signaling in colonic epithelial cell differentiation. Nat Genet. 2004;36:277-82.

Van den Brink GR, Hardwick JCH, Nielsen C, Xu C, ten Kate FJ, Glickman L van Deventer SJH, Roberts DJ, Peppelenbosch MP. Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract. Gut. 2002;51:628-33.

Van Dop WA, Uhmann A, Wijgerde M, Sleddens-Linkels E, Heijmans J, Offerhaus GJ, Weerman VDB, Boeckxstaens GE, Hommes DH, Hardwick JC, Hahn H, Van den Brink GR. Depletion of the colonic epithelial precursor cell compartment upon conditional activation of the hedgehog pathway. Gastroenterology. 2009;136:2195-203.

Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, Gervaz P, Ruiz i Altaba A. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009;1:338-51.

Varnat F, Siegl-Cachedenier I Malerba M, Gervaz P and, Ruiz i Altaba A. Loss of WNT-TCF addiction and enhancement of HH-GLI1 signalling define the metastatic transition of human colon carcinomas. EMBO Mol Med. 2010;2:1-18.

Woessner JF Jr. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 1991;5:2145-54.

Wang LH, Choi YL, Hua XY, Shin YK, Song YJ, Youn SJ, Yun HY, Park SM, Kim WJ, Kim HJ, Choi JH, Kim SH. Increased expression of sonic hedgehog and methlation of its promoter region in gastric cancer and its related lesion. Mod Pathol. 2006;19:675-83.

Wang JH, Manning BJ, Wu QD, Blankson S, Bouchier-Hayes D, Redmond HP. Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol. 2003;170:795-804.

Wasson GR, McGlynn AP, McNulty H. Global DNA and p53 region-specific hypomethylation in human colonic cells is induced by folate depletion and reversed by folate supplementation. J Nutr. 2006;136:2748-53.

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A, Weinberg RA. Twist, a master regulatorof morphogenesis, plays an essential role in tumor metastasis. Cell. 2004;117:927-39.

Yoo YA, Kang MH, Kim JS, Oh SC. Sonic hedgehog signaling promotes motility and invasiveness of gastric cancer cells through TGF-beta-mediated activation of the ALK5-Smad 3 pathway. Carcinogenesis. 2008;29:480-90.

Zhu Y, James RM, Peter A, Lomas C, Cheung F, Harrison DJ, Bader SA. Functional smoothened is required for expression of Gli3 in colorectal carcinomas cell. Cancer Lett. 2004;207:205-14.









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