摘要
目的:
鼻咽癌是一种上皮源性恶性肿瘤,绝大多数属于低分化鳞状细胞癌,恶性程度高,早期易发生淋巴结和全身远处转移,具有相当高的死亡率。鼻咽癌的发病机制尚未明确。本研究旨在根据本科室已有鼻咽癌基因表达谱芯片结果,寻找鼻咽癌组织与正常粘膜组织间的异常表达基因,利用生物信息学方法筛选参与鼻咽癌的信号转导相关基因,并采用相关分子生物学实验初步验证筛选出鼻咽癌信号转导相关基因在鼻咽癌组织中的表达情况。
方法:
本研究采用本科室已有深圳微芯公司基于玻片的包含8046个人类基因的基因芯片结果,初步获得鼻咽癌异常表达基因;进而结合GO分类从基因芯片异常表达的基因中筛选信号转导相关基因;以Biocarta信号通路数据库查询筛选基因相关转导信号通路信息,结合文献进一步分析在鼻咽癌发生发展过程中信号转导相关基因相关信息。进而进一步利用分子生物学实验real-time q-PCR验证筛选出鼻咽癌信号转导相关基因在鼻咽癌组织与鼻咽炎组织中的表达情况。
结果:
1.以鼻咽癌基因芯片结果为基础,在鼻咽癌组织获得1214个异常用表达基因,其中高表达的基因有871个;在鼻咽癌组织低表达的基因343个。
2.发现鼻咽癌差异表达基因中共有28个差异表达基因与细胞的信号转导相关,其中表达上调的21个,表达下调的7个,它们是:NRG2、SCYA3、PDGFA、SCYA18、SCYB10、SCYA4、INHBA、SCYA2、SCYA13、EFNA1、SFRP1、IL1A、HDGF、DKK1、TNFSF7、ECGF1、TNFSF4、NRTN、GRN、S100A9、MIF、IGFBP5、GRO1、SDF1、IGF2、C3、PTN、SEL1L。
3.从单个基因的信号通路的角度,我们得到了7个信号转导相关基因的相应信号转导通路信息,它们可能在鼻咽癌的发生发展中起重要作用。
4.通过应用实时荧光定量PCR(real-time quantitative PCR)技术对PDGFA和MIF两个基因在鼻咽癌组织中的表达进行检测,我们发现PDGFA和MIF两个基因在鼻咽癌组织中的表达比鼻咽炎组织高,这与基因芯片结果一致。
结论:
1.建立一种利用具有组织特异性鼻咽癌基因表达谱,进一步并利用生物信息学方法筛选鼻咽癌中信号转导相关基因的方法。
2.鼻咽癌异常表达的信号转导相关基因介导通路在鼻咽癌的发生、发展中可能具有重要意义,PDGFA和MIF两个基因在鼻咽癌组织中表达异常得以明确。为阐明鼻咽癌的发病机制,鼻咽癌早期诊断、基因治疗及预后的进一步研究提供依据与参考。
Objective:
Nasopharyngeal carcinoma(NPC) is one of epithele origin malignant tumor, most of them are poorly differentiated squamous-cell carcinoma, and the cancer cell will reach the lymphadens of all over the body, and the death rate is very high.While the pathogenesy of NPC is unclear now. This study was to screen signal transduction -regulated genes from gene chips in NPC and then make a preliminary identification of the Candidate Gene.
Methods:
A preliminary selection of abnormal expression genes from the gene chips of the Shenzhen Weixin company which detected the seven nasopharyngeal carcinoma and one rhinopharyngitis. And then to integrate the data of signal transduction -regulated by Gene Ontology, screen signal transduction -regulated genes from gene chips in NPC from BioCarta,make a preliminary identification of the Candidate Gene by real-time quantitative PCR..
Result:
1.In the basic of gene chips, there are 871 high expression genes and 343 low expression genes in the nasopharyngeal carcinoma tissue.
2.There are 27 differential expression relate gene of signal conducting.21 of them are high expressing and 7 are low express.They are NRG2、SCYA3、PDGFA、SCYA18、SCYB10、SCYA4、INHBA、SCYA2、SCYA13、EFNA1、SFRP1、IL1A、HDGF、DKK1、TNFSF7、ECGF1、TNFSF4、NRTN、GRN、S100A9、MIF、IGFBP5、GRO1、SDF1、IGF2、C3、PTN、SEL1L。
3.We accepted 7 signal transduction -regulated genes from BioCarta which could play important role in the development of NPC. And we got several signal pathways.
4.We found that the two gene PDGFA and MIF high expressed in NPC,and that was according to the gene chips.
Conclusion:
1.We found a new way how to screen signal transduction-regulated genes from gene chips in NPC and then make a preliminary identification of the Candidate Gene.
2.The differential expression relate gene PDGFA and MIF play an important role in the nasopharyngeal carcinoma’s emerging. And our study can be helpful in the pathogenetic and the gene therapy of nasopharyngeal carcinoma.
引文
[1] Ehrlich P. Uber den jetzigen Stand der Karzinomforschung. Ned Tijdschr Geneeskd, 1909, 5: 273~290.
[2]姚开泰.从死因回顾调查资料看湖南省鼻咽癌流行病学的一些特点并探索其发病机理。湖南医学院学报,1982:7(1)10-16
[3] Cohen JI.The biology of Epstein-Barr virus: lessons learned from the virus and the host. Current Opinion in Immunology 1999, 11:365-370
[4] Faulkner GC, Krajewski AS, Crawford DH: The ins and outs of EBV infection. Trends in Micorbiology 2000,185(4):
[5] Lo KW, Teo PM, Hui AB,et al. High resolution allelotype of microdissected primary nasopharyngeal carcinoma. Cancer Res.. 2000, 60: 3348-3353.
[6] Hui AB, Lo KW, Leung SF, et al. Detection of recurrent chromosomal gains and losses in primary nasopharyngeal carcinoma by comparative genome hybridization. Int. J. Cancer, 1999, 48: 498-503
[7] Lo KW, To KF, Huang DP. Focus on nasopharyngeal carcinoma. Cancer Cell,2004, 5: 423~425.
[8] Snijiders AM, Meijier GA, Brakenhoff RH, et al: Microarray techniques in pathology: tool or toy? J Clin Pathol: Mol Pathol 2000, 53:289-294
[9] [ Hiroshi Inoue, Ayumi Matsuyama, Koshi Mimori, et al: Prognostic Score of Gastric Cancer Determined bycDNA Microarray. Clinical Cancer Research.2002 Nov 8:3475-3479
[10] Haiyong Han, David J. Bearss, L. Walden Browne, et al: Identification of Differentially Expressed Genes in Pancreatic Cancer CellsUsing cDNA Microarray. CANCER RESEARCH . 2002 May 62:2890–2896
[11]何志巍,任彩萍,许亮国,等。用微阵列研究鼻咽癌与正常鼻咽组织基因表达谱。科学通报1999,44(23):2528-2531
[12] Rincon-Orozco B, Kunzmann V, Wrobel P, et a1. Activation of Vγ9Vδ2T cells by NKG2D. Immunology, 2005, 175:2144~2l51.
[13]李靖;徐勇;巨噬细胞移动抑制因子(MIF)与妇科恶性肿瘤的相关性研究国际泌尿系统杂志, 2006年05期656-658
[14]万波,刘玉明等.膀胱移行细胞癌中MIF、MMP9的表达及意义.2007年24卷4期
[15] Revillion F,Lhotellier V, Hornez L, et al ErbB/HER ligands in human breast cancer,and relationships with their receptors,the bio-pathological features and prognosis. Annals of Oncology. 2008 January:19(1):73-80.
[16] Dunn M,Sinha P,Campbell R,Blackburn E, et al Co-expression of neuregulins 1, 2, 3 and4 in human breast cancer. Journal of Pathology. 2004 Jun:203(2):672-80,
[17] Pignatelli M, Cortes-Canteli M, Lai C. Santos A, Perez-Castillo A, The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells. Journal of Cell Science. 2001 Nov:114(Pt 22):4117-26,
[18] [Gotzmann, J ,Fischer, A NM.et al A crucial function of PDGF in TGF-[beta]-mediated cancer progression of hepatocytes. Oncogene. 2006 May 25 :25(22):3170-3185.
[19] Bos, R,van Diest, P J,de Jong, J S , et al Hypoxia-inducible factor-1[alpha] is associated with angiogenesis, and expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathology. 2005 January 46(1):31-36.
[20] Donnem, Tom MD, Al-Shibli, Khalid MD et al Prognostic Impact of Fibroblast Growth Factor 2 in Non-small Cell Lung Cancer: Coexpression with VEGFR-3 and PDGF-B Predicts Poor Survival. Journal of Thoracic Oncology 2009 March 23 .
[21] Nakamura Y. Tanaka F. Yoshikawa Y. Mimori K. Inoue H. Yanaga K. Mori M. PDGF-BB is a novel prognostic factor in colorectal cancer. Annals of Surgical Oncology. 2008 Aug: 15(8):2129-36.
[22] Matei D. Kelich S. Cao L. Menning N. Emerson RE. Rao J. Jeng MH. Sledge GW. PDGF BB induces VEGF secretion in ovarian cancer. Cancer Biology & Therapy. 2007 Dec: 6(12):1951-9.
[23] Grimm C. Kantelhardt E. Heinze G. Polterauer S. Zeillinger R. Kolbl H. Reinthaller A. Hefler L. The prognostic value of four interleukin-1 gene polymorphisms in Caucasian women with breast cancer: a multicenter study. BMC Cancer. 2009,9:78.
[24] Hefler LA. Ludwig E. Lebrecht A. Zeillinger R. Tong-Cacsire D. Koelbl H. Leodolter S. Tempfer CB. Polymorphisms of the interleukin-1 gene cluster and ovarian cancer. Journal of the Society for Gynecologic Investigation. 2002 Nov-Dec:9(6):386-90.
[25] Engels EA, Wu X, Gu J, Dong Q, Liu J, Spitz MR . Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer Cancer Research. 2007 Jul 1:67(13):6520-7.
[26] Fahrig, Rudolf a, Quietzsch, et al. RP101 improves the efficacy of chemotherapy in pancreas carcinoma cell lines and pancreatic cancer patients. Anti-Cancer Drugs. 2006 October 17(9):1045-1056.
[27] [ 27 ] Baillat G. Garrouste F. Remacle-Bonnet M. Marvaldi J. Pommier G. Bcl-xL/Bax ratio is altered by IFNgamma in TNFalpha- but not in TRAIL-induced apoptosis in colon cancer cell line. Biochimica et Biophysica Acta. 2005 Aug 15, 1745(1):101-10.
[28] Meyer-Siegler, K L et al. Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidence Genes & Immunity. 2007 December 8(8):646-652.
[29] He X-X , Yang, J et al.Increased epithelial and serum expression of macrophage migration inhibitory factor (MIF) in gastric cancer potential role of MIF in gastric carcinogenesis: Gut.2006 June 55(6):797-802.
[30] Shkolnik, Tamar Ph.D. et al.The macrophage migration inhibition (MIF) assay as a marker of colorectal cancer: Studies in patients with colorectal cancer, noncolonic neoplasms, and conditions predisposing to colorectal cancer. Diseases of the Colon & Rectum. 1987 February 30(2):101-105.
[31] Deftos LJ. Granin-A. parathyroid hormone-related protein, and calcitonin gene products in neuroendocrine prostate cancerProstate - Supplement. 1998, 8:23-31.
[32] Huh, Jung-Im ,Calvo, A et al.Inhibition of VEGF receptors significantly impairs mammary cancer growth in C3(1)/Tag transgenic mice through antiangiogenic and non-antiangiogenic mechanisms.Oncogene.2005 January 27, 24(5):790-800.
[33] Yang, S L , et al.Transient receptor potential channel C3 contributes to the progression of human ovarian cancer.Oncogene. 2009 March 12, 28(10):1320-1328.
[34] Andoh, Akira; Shimada, et al. Transforming Growth Factor-[beta]1 Acts as a Potent Inhibitor of Complement C3 Biosynthesis in Human Pancreatic Cancer Cell Lines. Pancreas. 2000 March 20(2):138-145.
[35] Yoshidome K. Shibata MA. Maroulakou IG. Liu ML. Jorcyk CL. Gold LG. Welch VN. Green JE.Genetic alterations in the development of mammary and prostate cancer in the C3(1)/Tag transgenic mouse model International Journal of Oncology. 1998 Feb:12(2):449-453.
[36] Archimandritis A. Theodoropoulos G. Tryphonos M. Germenis A. Tjivras M. Kalos A. Fertakis A. Serum protein markers (Hp, GC, C3) in patients with colon cancer. Human Heredity. 1993 Jan-Feb 43(1):66-8.
[37] Campa D. Vodicka P. Pardini B. Novotny J. Forsti A. Hemminki K. Barale R. Canzian F.Could polymorphisms in ATP-binding cassette C3/multidrug resistance associated protein 3 (ABCC3/MRP3) modify colorectal cancer risk?European Journal of Cancer.2008 Apr 44(6):854-7.
[38] VARSANO S,RASHKOVSKY, et al. Human lung cancer cell lines express cell membrane complement inhibitory proteins and are extremely resistant to complement-mediated lysis; a comparison with normal human respiratory epithelium in vitro, and an insight into mechanism(s).Clinical & Experimental Immunology. 1998 August 113(2):173-182.
[39] Lockhart,D.J.et al.Expression monitoring by hybridization to high-density oligonucleotide arrays. NatureBiotechnol. 1996,14:1675-1680
[40] Dunphy CH.Gene expression profile data in lymphoma and leukemia:review of the literature andextrapolation of pertinent clinical applications.Arch Pathol Lab Med.2006;130(4):483-520
[41] Yano K.IMAI K,Shimizu A,et al.A new method for gene discovery in large-scale microarray data.Nucleic Acids Res.2006;34(5):1532-9.
[42] Steven I.Wang,Hasan Mukhtar.Gene expression profile in human prostate LNCaP cancercells by(-)epigallocatechin-3gallate[J].Cancer Letters 182,2002,43–51
[43] Ratna Chakrabarti,Liza D.Robles,Jane Gibson,et al.Profiling of differential expression of messenger RNA in normal,benign,and metastatic prostate cell lines[J].Cancer Genetics and Cytogenetics 139,2002,115–125
[44] Philip A.Cornford,2 Andrew R.Dodson,Keith F.Parsons,et al.Heat Shock Protein Expression Independently Predicts Clinical Outcome in Prostate Cancer[J].CANCER RESEARCH 60,December 15,2000,7099–7105
[45] Knight-Krajewski S,Welsh CF,Liu Y,et al Deregulation of the Rho GTPase,Rac1,suppresses cyclin-dependent kinase inhibitor p21CIP1 levels in androgen-independent human prostate cancer cells[J].Oncogene,2004,1–10
[46] Li-Fen Lee,Maggie C Louie,Sonal J Desai,et al.Interleukin-8 confers androgen-independent growth andmigration of LNCaP:differential effects of tyrosine kinases Src and FAK[J].Oncogene,2004,23,2197–2205
[47] Debouck C, Goodfellow PN.DNA microarrays in drug discovery and development. Nat Genet 21: 48–50.
[48] Heldin NE,Cvejic D,et al.Coexpression of functionally active receptor for thyrotropin and plate-dreived growth factor in huamn thyroid carcinoma cells. Endocrinology 1999 129(4):2187
[49] Rubin M,Wemer H,ert al.Platelat-derived growth factor-1(IGF-1) receptor gene.Exp cell Res.1994,211(2):374
[50] SwoPe MD , Lolis MacroPhage migration inhibitory factor:cytokine , hormone or enzyme?Rev Physiol Bioehem Pharmacol.1999;139:l-32.
[51] Baugh JA.Bucala R.MacroPhage migration inhibitory factor.Crit Care Med.2002;30:s27-s35.doi:10.1097/00003246-200201001-00004.
[52] SunHW,Bernhaagen J,Bueala R,etal.Crystal structure at2.6 A resolution of human macroPhage migration inhibitory factor..PNAS,1996,93:5191-5196.
[53] Mtehell RA,Baeher M,Bwenhage J,etal.Cloning and characterization of the gene for mous macroPhage migration inhibitory factor(MIF).[J].Immunol,1985,54:3863-3870.
[54] Mitehel RA,Bueala R.Tumor growth-Promoting ProPerties of macroPhage migration inhibitory factor(MIF)[J].SeminCaneerBiol,2000.10(5):359-366.
[55] Hudson JD,Shoaibi MA,Maestro R,etal.AProflammatory cytokine inhibits P53 tumor suPPressor activity[J].JExPMed,1999,190(10):1375-1382.
[56] RBueala.MIF,a Previously unreeognized Pituitary hormone and macroPhage cytokine,is a Pivotal mediator in endotoxic shock.CireShock,1994;9,44(l):5-39.
[57] CalandraT , BemhagenJ , tehellRA , etal.ThemacroPhage15animPortantnd Previously unreeognized source of macroPhage migration inhibitory faetorJ.xP.Med.,
[58] White ES,Flaherty KR,Carskadon S,etal.MacroPhage migration inhibitory faetorandCXC chemokinees Pression in non-small cell lung cancer role in angiogenesisandPrognosis[J]. ClinCaneerRes,2003,(9):853-860.
[59] Him E,Ono T,Dhar DK,etal.overexePression of macroPhage migration inhibitory factor induces angiogenesis and deteriorates Prognosi safter radiealResection for hepatocellular careinoma[J].Caneer2005,103(3):588-595.
[60] XiaHH,ZhangST,LamSK,etal.ExePression of macroPhage migration inhibitoryFactor in esoPhagcal squamous cell carcinoma ande ffeets of bileacids and NSAIDs[J].Careinogenesis,2005,26(l):11-15.
[61] SuzukiF,NakamanuY,oridateN,etal.Prognostie significanee of cytoPlasmie maeroPhage migration inhibitory factor exPression in Patients with aquamous cell Careinoma of the head and neck treated with coneurrent chemoradiotheraPy [J].oneolReP , 2005 ,13(l):59-64.994;7,179:1895-1902.
[62] RenY,ChanHM,LIZ,etal.UPregUlation of maeroPhage migration inhibitory Faetor contributes to induced N-Myc exPression by the activation of ERK Signaling Pathway and increzsed exPression of interleukin 28 and VEGF in neuroblastoma.oneogene,2004,23(23):4146-4154.
[63] JinZQ,ZhiFC,ChenXQ,etal.ExPression of maeroPhage migration inhibition factor in Panereatieear cinoma tissue.DiYiJunDaXueXueao,2004,24(11):1301-1303.
[64] Repp AC , Mayhew ES,et al.Human uveal melanoma cells produce maeroPhage migration-inhibitory factor to Prevent lysis by NKeells.J-Immunol.20007 ,15;165(2):710-715.
[65] Xia HH,Zhang ST,Lam SK,etal.ExPression of maeroPhage migration in hibitory Factor in esoPhageal squamou ceell careinoma and effects of hileacids and NSAID.Careinogenesis,2005,26:11-15.
[66] He XX,Yang J,Ding YW,etal.Increased epithelial and serum expression of maeroPhage migration inhibitoty factor in gastric cancer:Potential role of MIF in gastric careinogenesis.Gut 2006,4,(17):EPub ahead of Print.
[67] Kamimura A,Kamaehi M,Nishihira J,etal.Intracellular Distribution of maeroPhage migration inhibitory factor Prediets the Prognosis of Patients with Adenocareinoma of the lung.CaneerJul2000;89(2):334-341.
[68]刘玉明,将先镇。MIF基因在膀肤癌组织中的表达及其反义表达载体对膀肤癌细胞生物学效应的研究。
[69] PetrovskyN,BucalaR.MacroPhage migration inhibitory factor:acritieal Neuro humoral mediator.FrontHormRes,2002,29:83-90.
[70] Petrenkoo,Fingerle Rowson G,Peng T,etal.MaeroPhage migration inhibitory Factordefieieney 15 assoeiated with transformation.JBiolChem,2003,278(13): 11078-11085.
[71] ChaPman RW, Annoneol CaPn7:a highly diver gentverte brateeal Painwitha novelC-terminaldomainl999;10(suPP14):308-311.
[72] Fingerle-RowsonG,PetrenkoO,MetzCN,etal.theP53 dePendent effects of macroPhage migration inhibitory factor revealed by gene targeting.PANS,2003,100:9354-9359.
[73] ChatehellRA.Mechanisms and effectors of MIF-dependent promotion of Tumourigenesis Cellular Signalling,2004,16:13-19.
[74] Fingerle-RowsonG,Petrenkoo,MetzCN,etal.theP53-dePendeent effects of macroPhage migration inhibitory factor revealed by genetargeting.PANS,2003,100:9354-9359.
[75] HoY,SasakiY,HOrimotoM,etal.Activation of mitogenactivated proteinkinases/a raeellular signal-regulated kinases in human hePatoeellulareareinoma. HePatology , 1998 ,27:951-958.
[76] WiesenauerCA,YIP-SehneiderMT,WangY,atal.MutiPlean tieaneer effects of blocking、IEK-ERK signaling inhePatocellularcarcinoma.JAmCollSurg,2004,198:410-421.
[77] OleksiP , UteMM.MacroPhage migration inhibitory factor MIF in tres with The Rb-EZFPathway.MoleeularCell,2005,17,225-236.
[78] LueH , KaPumiotuA.FingerleRowsonG , etal.RaPidand transient activation of The ERK/MAPK signalling Pathway by macroPhage migration inhibitory Factor (MIF)and dePendence on JAB1/CSNS and Srekinase activity.Cell Signal,2006,18(5):688-703.
[79] JinzQ,zhiFC,ChenXQ,etal.ExPression of macroPhage migration inhibitionFactor in Pancreatie carcinoma tissue.DiYiJunYiDaxuexuebao,2004,24(11):1301-1303.
[1] Gires O ,Kohlhuber F,Kilger E ,et al . Latent membrane protein 1 of Epstein-Barr virus interacts with JAK3 and activates STAT proteins[J ] .EMBO J,1999,18(11) : 3064- 3073.
[2] Wang F , Gregory C , Sample C et al . J Virol , 1990 ;64 :2309
[3] Huen DS , Henderson SA , Croon - Carter D et al . Oncogene ,1995 ; 10 : 549 - 560
[4] Mosiialos S , Sarma V , Lin Z et al . Cell , 1995 ;80 :389 - 399
[5] Nioholson L , J Hopwood P , Johannessen I et al . Oncogene ,1997 ; 15 :275 - 283
[6] Uchida J , Yasui T , Takaoka-Shichijo Y, et al .Mimicry of CD40 signals by Epstein-Barr virus LMP1 in B lymphocyte responses [J ] . Science , 1999 ,286(5438) :300-303.
[7] Kaykas A , Worringer K, Sugden B. CD40 and LMP-1 both signal from lipid rafts but LMP-1 assembles a distinct , more efficient signaling complex[J ] . EMBO J 2001 ,20 (11) :2641-2654.
[8] Chan FK, Chun HJ , Zheng L , et al . A domain in TNF receptors thatmediates ligand-independent receptor assembly and signaling [ J ] . Science ,2000 ,288(5475) :2351- 2354.
[9] Rothenberger S , RousseauxM, Knecht H , et al . Association of the Epstein-Barr virus latent membrane protein 1 with lipid rafts is mediatedthrough its N-terminal region[J ] . Cell Mol Life Sci ,2002 ,59 (1) :171-180.
[10] Lustig B , Behrens J . The Wnt signaling pathway and its role in tumor development [ J ] Cancer Res Clin Oncol , 2 0 0 3 ,1 2 9 ( 4 ) : 1 9 9 - 2 2 1.
[11] Alexandra Schambony , Martin Kunz , Dietmar Gradl. Cross regulation of Wnt signaling and cell adhesion [ J ] . International Society of Differentiation , 2 0 0 4 , 7 2 ( 7 ) : 3 0 7 -3 1 8.
[12] Lin YC , You L , Xu Z , et al. Wnt signaling activation andW IF 21 silencing in nasopharyngeal cancer cell lines [ J ] .Biochem Biophys Res Commun , 2 0 0 6 , 3 4 ( 1 2 ) : 6 3 5 -6 4 0.
[13] Sriuranpong V , Mutirangura A , Gillesp ie JW , et al. Globlegene exp ression p rofile of nasopharyngeal carcinoma by lasercap ture microdissection and comp lemantary DNA microarrays[ J ] .Clin Cancer Res , 2 0 0 4 , 1 0 ( 1 5 ) : 4 9 4 4 -4 9 5 8.
[14] Zeng ZY , Zhou YH , Zhang WL , et al. Gene exp ression profiling of nasopharyngeal carcinoma reveals the abnormallyregulated Wnt signaling pathway[ J ] . Hum Pathol , 2 0 0 7 ,3 8 ( 1 ) : 1 2 0 - 1 3 3. .
[15] Subramanian G, Schwarz R E , Higgins L , et al . Targeting endogenous transforming growth factor beta receptor signaling in SMAD42deficient pancreatic carcinoma cells inhibit s their invaaive phenotypel [J ] . Cancer Res ,2004 ,64 (15) :5200 - 5211.
[16] Shi Y. St ructural insight s on Smad function in TGF-beta signaling[J ] . Bioessays ,2001 ,23 (3) :223 - 232.
[17] Hatal A. TGF2beta signaling and cancer [J ] . Exp CellRes ,2001 ,264 (1) :111 - 116.
[18] Moustakas A , Souchelnyt skyi S , Heldin C H. Smadregulation in TGF-beta ignalat ransduetion [J ] . J CellSci ,2001 ,114 ( Pt 24) :4359 - 4369.
[19] Rooke H M , Crosier K E. The Smad proteins andTGF-beta signalling :uncovering a pathway critical in cancer [J ] . Pathology ,2001 ,33 (1) :73 - 84.
[20] Massague J , Chen Y G. Cont rolling TGF-beta signalling. Genes Dev ,2000 ,14 (6) :627 - 644.
[21] Massague J , Blain S W , Lo R S. TGF-beta signaling in growth conlorl , cancer , andheritable disorders[J ] .Cell ,2000 ,103 (2) 295 - 309.
[22] Staller P , Peukert K, Kiermaier A , et al . Repressionof p15INK4b expression by Myc through association withMiz21[J ]. Nature Cel Biology ,2001 ,3 (4) :392 - 399.
[23] Maurice D , Pierreux C E , Howell M , et al . Loss ofSmad4 function in pancreatic tumors : C2terminal t runcation leads to decreased stability [ J ] . J Bilo Chem , 2001 ,276 (46) :43175 - 43181
[24] Miyakia M , Kuroki T. Role of Smad4 (DPC4) inactivation in human cancer [ J ] . Biochem Biophys Res Commun ,2003 ,306 (4) :799 - 804.
