Gene deregulation in gastric cancer.

Despite its decreasing frequency in the Western world during recent decades, gastric cancer is still one of the leading causes of cancer-related deaths worldwide. Due to the oligosymptomatic course of early gastric cancer, most cases are diagnosed in the advanced stages of the disease. The curative potential of current standard treatment continues to be unsatisfactory, despite multimodal approaches involving surgery, chemotherapy and radiotherapy. Novel therapeutics including small molecules and monoclonal antibodies are being developed and have been partially introduced into clinical use in connection with neoplastic diseases such as chronic myeloid leukemia, non-Hodgkin's lymphoma and colorectal cancer. Thorough understanding of the changes in gene expression occurring during gastric carcinogenesis may help to develop targeted therapies and improve the treatment of this disease. Novel molecular biology techniques have generated a wealth of data on up- and down-regulation, activation and inhibition of specific pathways in gastric cancer. Here, we provide an overview of the different aspects of aberrant gene expression patterns in gastric cancer.

[1]  H. Höfler,et al.  E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. , 1994, Cancer research.

[2]  M Oshima,et al.  Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. , 1999, Cancer research.

[3]  G. Tamura,et al.  The sequential accumulation of genetic alterations characteristic of the colorectal adenoma–carcinoma sequence does not occur between gastric adenoma and adenocarcinoma , 1995, The Journal of pathology.

[4]  C. Seva,et al.  Growth-promoting effects of glycine-extended progastrin. , 1994, Science.

[5]  S. Hirohashi,et al.  Dysadherin, a cancer-associated cell membrane glycoprotein, down-regulates E-cadherin and promotes metastasis , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  M. Braun,et al.  Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Kinzler,et al.  Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. , 1995, Science.

[8]  D. Pritchard,et al.  Gastrin-stimulated gastric epithelial cell invasion: the role and mechanism of increased matrix metalloproteinase 9 expression. , 2002, The Biochemical journal.

[9]  H. Yoo,et al.  Expression profiling and subtype-specific expression of stomach cancer. , 2003, Cancer research.

[10]  R. Nusse,et al.  β-catenin: a key mediator of Wnt signaling , 1998 .

[11]  M. Tatematsu,et al.  Gastric and Intestinal Phenotypic Expression of Human Stomach Cancers as Revealed by Pepsinogen lmmunohistochemistry and Mucin Histochemistry , 1990, Acta pathologica japonica.

[12]  Yan Xue,et al.  Inhibition of endothelial cell proliferation by targeting Rac1 GTPase with small interference RNA in tumor cells. , 2004, Biochemical and biophysical research communications.

[13]  D. Hanahan,et al.  Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis , 1996, Cell.

[14]  Il-Jin Kim,et al.  Identification of Genes with Differential Expression in Acquired Drug-Resistant Gastric Cancer Cells Using High-Density Oligonucleotide Microarrays , 2004, Clinical Cancer Research.

[15]  C. McConkey,et al.  Cancer of the stomach. , 1989 .

[16]  H. Yokozaki,et al.  Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype , 1999, International journal of cancer.

[17]  Yi Ding,et al.  Methylation and mutation analysis of p16 gene in gastric cancer. , 2003, World journal of gastroenterology.

[18]  D. Barber,et al.  Somatostatin, Acting at Receptor Subtype 1, Inhibits Rho Activity, the Assembly of Actin Stress Fibers, and Cell Migration* , 2002, The Journal of Biological Chemistry.

[19]  L. Hansson,et al.  Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. , 2001, Gastroenterology.

[20]  L. Kolonel,et al.  Gastric carcinoma , 2002, Cancer.

[21]  C. la Vecchia,et al.  Family history and the risk of stomach and colorectal cancer , 1992, Cancer.

[22]  David A Jones,et al.  Reactivating the expression of methylation silenced genes in human cancer , 2002, Oncogene.

[23]  V. Debailleul,et al.  Characterization of the human mucin gene MUC5AC: a consensus cysteine-rich domain for 11p15 mucin genes? , 1995, The Biochemical journal.

[24]  H. Forssell,et al.  Relationship between reduction of gastric acid secretion and plasma gastrin concentration during omeprazole treatment. , 1988, Scandinavian journal of gastroenterology.

[25]  E. Martinelli,et al.  The unsolved enigma of CDH1 down-regulation in hereditary diffuse gastric cancer. , 2004, The Journal of surgical research.

[26]  H. Watanabe,et al.  Cellular phenotypes of differentiated‐type adenocarcinomas and precancerous lesions of the stomach are dependent on the genetic pathways , 2000, The Journal of pathology.

[27]  E. Eisenhauer,et al.  DNA methyltransferase inhibitors-state of the art. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.

[28]  Y. Bang,et al.  Rapid induction of p21WAF1 but delayed down-regulation of Cdc25A in the TGF-β-induced cell cycle arrest of gastric carcinoma cells , 1999, British Journal of Cancer.

[29]  D. Graham,et al.  Inappropriate hypergastrinaemia in asymptomatic healthy subjects infected with Helicobacter pylori. , 1990, Gut.

[30]  H. Son,et al.  Abnormal Expression of E-cadherin in Early Gastric Carcinoma: Its Relationship with Macroscopic Growth Patterns and Catenin &agr; and &bgr; , 2004, Journal of clinical gastroenterology.

[31]  H. Friess,et al.  Concomitant Analysis of the Epidermal Growth Factor Receptor Family in Esophageal Cancer: Overexpression of Epidermal Growth Factor Receptor mRNA but Not of c-erbB-2 and c-erbB-3 , 1999, World Journal of Surgery.

[32]  E. Rodriguez-Boulan,et al.  Collagen receptors mediate early events in the attachment of epithelial (MDCK) cells , 1987, The Journal of Membrane Biology.

[33]  Il-Jin Kim,et al.  DNA microarray analysis of the correlation between gene expression patterns and acquired resistance to 5-FU/cisplatin in gastric cancer. , 2004, Biochemical and biophysical research communications.

[34]  K. Mafune,et al.  Highly specific marker genes for detecting minimal gastric cancer cells in cytology negative peritoneal washings. , 2004, Biochemical and biophysical research communications.

[35]  Takuma Sasaki,et al.  Expression of C‐erbB‐2 oncoprotein in gastric carcinoma. Immunoreactivity for C‐erbB‐2 protein is an independent indicator of poor short‐term prognosis in patients with gastric carcinoma , 1991, Cancer.

[36]  X. Yao,et al.  Expression of seven main Rho family members in gastric carcinoma. , 2004, Biochemical and biophysical research communications.

[37]  S. Natsugoe,et al.  Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[38]  S. Sato,et al.  Combined evaluation of mucin antigen and E‐cadherin expression may help select patients with gastric cancer suitable for minimally invasive therapy , 2003, The British journal of surgery.

[39]  C. Nobes,et al.  Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia , 1995, Cell.

[40]  R. Haas,et al.  Identification and Characterization of Helicobacter pylori Genes Essential for Gastric Colonization , 2003, The Journal of experimental medicine.

[41]  E. Hahn,et al.  Expression of hepatocyte growth factor, transforming growth factor alpha, apoptosis related proteins Bax and Bcl‐2, and gastrin in human gastric cancer , 2001, Alimentary pharmacology & therapeutics.

[42]  S. Jordan,et al.  Abnormal immunoreactivity of the E-cadherin-catenin complex in gastric carcinoma: relationship with patient survival. , 1997, Gastroenterology.

[43]  Y. Kim,et al.  Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. , 1995, Cancer research.

[44]  Y. Bang,et al.  Up‐regulation of human telomerase catalytic subunit during gastric carcinogenesis , 1999, Cancer.

[45]  R. Seruca,et al.  Cytogenetic findings in eleven gastric carcinomas. , 1993, Cancer genetics and cytogenetics.

[46]  M. Lübbert,et al.  Upstream and downstream targets of RUNX proteins , 2003, Journal of cellular biochemistry.

[47]  E. Tahara Genetic pathways of two types of gastric cancer. , 2004, IARC scientific publications.

[48]  M. Thun,et al.  Aspirin use and risk of fatal cancer. , 1993, Cancer research.

[49]  S. Hirohashi,et al.  Clinical Significance of Dysadherin Expression in Gastric Cancer Patients , 2004, Clinical Cancer Research.

[50]  T. Wang,et al.  Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. , 2000, Gastroenterology.

[51]  S. Kitano,et al.  Increased DNA methyltransferase 1 (DNMT1) protein expression correlates significantly with poorer tumor differentiation and frequent DNA hypermethylation of multiple CpG islands in gastric cancers. , 2004, The American journal of pathology.

[52]  B. Jenkins,et al.  Gastric cancer development in mice lacking the SHP2 binding site on the IL-6 family co-receptor gp130. , 2004, Gastroenterology.

[53]  Y. Joo,et al.  Cyclooxygenase-2 Expression Is Associated with Well-Differentiated and Intestinal-Type Pathways in Gastric Carcinogenesis , 2003, Digestion.

[54]  R. Foisner,et al.  E-cadherin regulates cell growth by modulating proliferation-dependent β-catenin transcriptional activity , 2001, The Journal of cell biology.

[55]  Tsung-Teh Wu,et al.  Genetic Alterations in Gastric Adenomas of Intestinal and Foveolar Phenotypes , 2003, Modern Pathology.

[56]  K. Kinzler,et al.  Frequency of Smad gene mutations in human cancers. , 1997, Cancer research.

[57]  M. Shin,et al.  Inactivating mutations of the caspase-10 gene in gastric cancer , 2002, Oncogene.

[58]  M. S. Lee,et al.  c-Myc expression is related with cell proliferation and associated with poor clinical outcome in human gastric cancer. , 1999, Journal of Korean medical science.

[59]  Hoguen Kim,et al.  Transcriptional silencing of the RUNX3 gene by CpG hypermethylation is associated with lung cancer. , 2004, Biochemical and biophysical research communications.

[60]  T. Cover,et al.  Cell Vacuolation Induced by the VacA Cytotoxin ofHelicobacter pylori Is Regulated by the Rac1 GTPase* , 2000, The Journal of Biological Chemistry.

[61]  Kohei Miyazono,et al.  TGF-β signalling from cell membrane to nucleus through SMAD proteins , 1997, Nature.

[62]  H. Frierson,et al.  Expression profiling of gastric adenocarcinoma using cDNA array , 2001, International journal of cancer.

[63]  T. Irimura,et al.  Expression of MUC1 and MUC2 mucins in gastric carcinomas: its relationship with the prognosis of the patients. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[64]  H. S. Kim,et al.  Somatic mutations of the trefoil factor family 1 gene in gastric cancer. , 2000, Gastroenterology.

[65]  W. Birchmeier,et al.  Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. , 1994, Biochimica et biophysica acta.

[66]  Anthony E. Reeve,et al.  E-cadherin germline mutations in familial gastric cancer , 1998, Nature.

[67]  B. Finlay,et al.  Helicobacter pylori Infection Targets Adherens Junction Regulatory Proteins and Results in Increased Rates of Migration in Human Gastric Epithelial Cells , 2004, Infection and Immunity.

[68]  J. Yokota,et al.  Mutation analysis of the Smad2 gene in human colon cancers using genomic DNA and intron primers. , 1998, Carcinogenesis.

[69]  S. Hirohashi Inactivation of the E-cadherin-mediated cell adhesion system in human cancers. , 1998, The American journal of pathology.

[70]  J. Herman,et al.  Gene silencing in cancer in association with promoter hypermethylation. , 2003, The New England journal of medicine.

[71]  Y. Okada,et al.  Expression and tissue localization of matrix metalloproteinase 7 (matrilysin) in human gastric carcinomas. Implications for vessel invasion and metastasis , 1998, International journal of cancer.

[72]  H. Lee,et al.  Altered expression and mutation of β‐catenin gene in gastric carcinomas and cell lines , 2001 .

[73]  G. Dockray,et al.  Gastrin-cholecystokininB receptor expression in AGS cells is associated with direct inhibition and indirect stimulation of cell proliferation via paracrine activation of the epidermal growth factor receptor , 2002, Gut.

[74]  M. Rhyu,et al.  Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. , 2002, The American journal of pathology.

[75]  Y. Bang,et al.  Truncation of the TGF-β type II receptor gene results in insensitivity to TGF-β in human gastric cancer cells , 1999, Oncogene.

[76]  T. Merriman,et al.  Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer , 2002, Oncogene.

[77]  C. Chi,et al.  Clinical implications of chromosomal abnormalities in gastric adenocarcinomas , 2002, Genes, chromosomes & cancer.

[78]  Y. Hayashizaki,et al.  Differential gene expression profiles of gastric cancer cells established from primary tumour and malignant ascites , 2002, British Journal of Cancer.

[79]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[80]  Mitsuru Sasako,et al.  Focus on gastric cancer. , 2004, Cancer cell.

[81]  N. Bouck,et al.  How tumors become angiogenic. , 1996, Advances in cancer research.

[82]  H. Kuwano,et al.  No mutations of the Smad2 gene in human sporadic gastric carcinomas. , 1999, Japanese journal of clinical oncology.

[83]  K. Takada Epstein-Barr virus and gastric carcinoma , 2000, Molecular pathology : MP.

[84]  S. Hirohashi,et al.  Overexpression of c‐erbB‐2 protein in gastric cancer. Its correlation with long‐term survival of patients , 1993 .

[85]  N. Peat,et al.  Molecular cloning and expression of human tumor-associated polymorphic epithelial mucin. , 1990, The Journal of biological chemistry.

[86]  B. Gumbiner,et al.  E-Cadherin Suppresses Cellular Transformation by Inhibiting β-Catenin Signaling in an Adhesion-Independent Manner , 2001, The Journal of cell biology.

[87]  N. Yamanaka,et al.  Relationship of C‐erbB‐2 protein expression and gene amplification to invasion and metastasis in human gastric cancer , 1993, Cancer.

[88]  Y. Kakeji,et al.  Overexpression of Vascular Endothelial Growth Factor C Is Related to Lymphogenous Metastasis in Early Gastric Carcinoma , 2001, Oncology.

[89]  C. Moskaluk,et al.  Gastric cancers overexpress S100A calcium-binding proteins. , 2002, Cancer research.

[90]  T. Tsukamoto,et al.  β‐Catenin gene alteration in glandular stomach adenocarcinomas in N‐methyl‐N‐nitrosourea‐treated and Helicobacter pylori‐infected Mongolian gerbils , 2004, Cancer Science.

[91]  Y. Bang,et al.  Loss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancer , 2004, Oncogene.

[92]  M. Katoh Frequent up-regulation of WNT2 in primary gastric cancer and colorectal cancer. , 2001, International journal of oncology.

[93]  D. Richel,et al.  Activation of the Canonical β-Catenin Pathway by Histamine* , 2003, Journal of Biological Chemistry.

[94]  Jia Liu,et al.  Frequent translocalization of beta-catenin in gastric cancers and its relevance to tumor progression. , 2004, Oncology reports.

[95]  L. Hansson,et al.  Decreasing incidence of both major histologic subtypes of gastric adenocarcinoma – a population-based study in Sweden , 2000, British Journal of Cancer.

[96]  W. Yasui,et al.  Human epidermal growth factor in gastric carcinoma as a biologic marker of high malignancy. , 1986, Japanese journal of cancer research : Gann.

[97]  C. Caldas,et al.  E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma , 2001, Oncogene.

[98]  P. Comoglio,et al.  c-met is amplified but not mutated in a cell line with an activated met tyrosine kinase. , 1991, Oncogene.

[99]  B. Gumbiner,et al.  The role of the cell adhesion molecule uvomorulin in the formation and maintenance of the epithelial junctional complex , 1988, The Journal of cell biology.

[100]  S. Semba,et al.  Molecular biological observations in gastric cancer. , 1996, Seminars in oncology.

[101]  K. Heider,et al.  Importance of different CD44v6 expression in human gastric intestinal and diffuse type cancers for metastatic lymphogenic spreading , 1995, Journal of Molecular Medicine.

[102]  J. Liu,et al.  Expression of hyaluronan receptors CD44 and RHAMM in stomach cancers: relevance with tumor progression. , 2000, International journal of oncology.

[103]  G. Baldwin,et al.  Gastrins, cholecystokinins and gastrointestinal cancer. , 2004, Biochimica et biophysica acta.

[104]  E. Li,et al.  Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases , 1998, Nature Genetics.

[105]  J. Issa,et al.  Changes in DNA Methylation in Neoplasia: Pathophysiology and Therapeutic Implications , 2001, Annals of Internal Medicine.

[106]  Y. Doki,et al.  Localization of IQGAP1 is inversely correlated with intercellular adhesion mediated by e‐cadherin in gastric cancers , 2001, International journal of cancer.

[107]  V. Devita,et al.  Cancer : Principles and Practice of Oncology , 1982 .

[108]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[109]  G. Asano,et al.  The correlation of epidermal growth factor with invasion and metastasis in human gastric cancer , 1990, The Japanese journal of surgery.

[110]  Yuan-yuan Li,et al.  Expression of mucins and E-cadherin in gastric carcinoma and their clinical significance. , 2004, World journal of gastroenterology.

[111]  Tytgat,et al.  Loss of E‐cadherin expression in early gastric cancer , 1999, Histopathology.

[112]  N. Rahman,et al.  Low frequency of germline E-cadherin mutations in familial and nonfamilial gastric cancer , 1999, British Journal of Cancer.

[113]  A. Lev-Tov,et al.  The Runx3 transcription factor regulates development and survival of TrkC dorsal root ganglia neurons , 2002, The EMBO journal.

[114]  A. Corfield,et al.  Mucins and mucosal protection in the gastrointestinal tract: new prospects for mucins in the pathology of gastrointestinal disease , 2000, Gut.

[115]  Ji-yeon Lee,et al.  Analysis of gene expression profiles of gastric normal and cancer tissues by SAGE. , 2003, Genomics.

[116]  K. Miyazono,et al.  Interaction and Functional Cooperation of PEBP2/CBF with Smads , 1999, The Journal of Biological Chemistry.

[117]  B. Geiger,et al.  Inhibition of β-catenin-mediated transactivation by cadherin derivatives , 1998 .

[118]  D. Shibata,et al.  Epstein-Barr virus-associated gastric adenocarcinoma. , 1992, The American journal of pathology.

[119]  X. F. Wang,et al.  Targeted Disruption of Smad3 Reveals an Essential Role in Transforming Growth Factor β-Mediated Signal Transduction , 1999, Molecular and Cellular Biology.

[120]  L. Shoshani,et al.  Molecular physiology and pathophysiology of tight junctions. I. Biogenesis of tight junctions and epithelial polarity. , 2000, American journal of physiology. Gastrointestinal and liver physiology.

[121]  M. Enjoji,et al.  Gastric lesions in familial adenomatosis coli: their incidence and histologic analysis. , 1978, Human pathology.

[122]  S. Hirohashi,et al.  p53 Mutation in gastric cancer: A genetic model for carcinogenesis is common to gastric and colorectal cancer , 1993, International journal of cancer.

[123]  R. Scott,et al.  BRCA2 gene mutations in families with aggregations of breast and stomach cancers , 2002, British Journal of Cancer.

[124]  Y. Nakajima,et al.  Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. , 2001, Anticancer research.

[125]  C. Boland,et al.  Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. , 1993, Gastroenterology.

[126]  R. Bronson,et al.  Gastric Hyperplasia in Mice Lacking the Putative Cdc42 Effector IQGAP1 , 2000, Molecular and Cellular Biology.

[127]  J. Willis,et al.  Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer , 2000, Nature Genetics.

[128]  J. Vass,et al.  Profiling, comparison and validation of gene expression in gastric carcinoma and normal stomach , 2003, Oncogene.

[129]  H. Büller,et al.  Transcriptional activation of the murine Muc5ac mucin gene in epithelial cancer cells by TGF-beta/Smad4 signalling pathway is potentiated by Sp1. , 2004, The Biochemical journal.

[130]  J. Yokota,et al.  The intracellular E-cadherin germline mutation V832 M lacks the ability to mediate cell–cell adhesion and to suppress invasion , 2003, Oncogene.

[131]  Izhak Haviv,et al.  Distinctive patterns of gene expression in premalignant gastric mucosa and gastric cancer. , 2003, Cancer research.

[132]  Min-Cheol Lee,et al.  Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. , 2002, The American journal of pathology.

[133]  W. Birchmeier,et al.  Met, metastasis, motility and more , 2003, Nature Reviews Molecular Cell Biology.

[134]  R. Seruca,et al.  E-Cadherin (CDH1) and p53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. , 2004, European journal of cancer.

[135]  O. Cummings,et al.  Inactivation of Smad4 in gastric carcinomas. , 1997, Cancer research.

[136]  Y. Bang,et al.  Transcriptional repression of the transforming growth factor-β type I receptor gene by DNA methylation results in the development of TGF-β resistance in human gastric cancer , 1999, Oncogene.

[137]  F. Borchard,et al.  Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene. , 1998, Pathology, research and practice.

[138]  Y. Mitani,et al.  Gene Expression Profile of Gastric Carcinoma , 2004, Cancer Research.

[139]  N. Sasaki,et al.  Helicobacter pylori infection and the development of gastric cancer. , 2001, The New England journal of medicine.

[140]  Jun Yu,et al.  Increased β-catenin mRNA levels and mutational alterations of the APC and β-catenin gene are present in intestinal-type gastric cancer , 2002 .

[141]  G. Sachs,et al.  Local pH elevation mediated by the intrabacterial urease of Helicobacter pylori cocultured with gastric cells. , 2000, The Journal of clinical investigation.

[142]  Birgit Luber,et al.  Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. , 2002, The American journal of pathology.

[143]  P. Lichter,et al.  Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2 , 1998 .

[144]  K. Kinzler,et al.  Serial Analysis of Gene Expression , 1995, Science.

[145]  C. Caldas,et al.  Genetic screening for hereditary diffuse gastric cancer , 2003, Expert review of molecular diagnostics.

[146]  M. Magnani,et al.  Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[147]  E. Hahn,et al.  Helicobacter pylori infection and gastrin and cyclooxygenase expression in gastric and colorectal malignancies , 2000, Regulatory Peptides.

[148]  K. Choe,et al.  Prognostic significance of the expression of Smad4 and Smad7 in human gastric carcinomas. , 2004, Annals of oncology : official journal of the European Society for Medical Oncology.

[149]  Shuichi Tsutsumi,et al.  Global gene expression analysis of gastric cancer by oligonucleotide microarrays. , 2002, Cancer research.

[150]  M. Loda,et al.  CDC25 phosphatases as potential human oncogenes. , 1995, Science.

[151]  S. Mundlos,et al.  Expression of Galectin-3 in Skeletal Tissues Is Controlled by Runx2* , 2003, The Journal of Biological Chemistry.

[152]  M. Ahn,et al.  Telomerase activity and its clinicopathological significance in gastric cancer. , 1997, European journal of cancer.

[153]  J. Houghton,et al.  Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. , 2004, Gene.

[154]  Scott E. Kern,et al.  DPC4, A Candidate Tumor Suppressor Gene at Human Chromosome 18q21.1 , 1996, Science.

[155]  C. Fenoglio-Preiser,et al.  TP53 and gastric carcinoma: A review , 2003, Human mutation.

[156]  A. Ristimäki,et al.  Cyclooxygenase‐2 expression during carcinogenesis in the human stomach , 2002, The Journal of pathology.

[157]  R. Kim,et al.  Expression and relationship between topoisomerase I and II alpha genes in tumor and normal tissues in esophageal, gastric and colon cancers. , 1999, Anticancer research.

[158]  C. Fenoglio-Preiser,et al.  beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. , 2002, Cancer research.

[159]  J. Herman,et al.  Aberrant methylation of gene promoters in cancer---concepts, misconcepts, and promise. , 2000, Journal of the National Cancer Institute.

[160]  W. Foulkes,et al.  Germline E-cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria , 2004, Journal of Medical Genetics.

[161]  I. Barshack,et al.  Human gastrin : A Helicobacter pylori-specific growth factor , 1999 .

[162]  W. Park,et al.  Inactivating mutations of the Siah-1 gene in gastric cancer , 2004, Oncogene.

[163]  S. Nishizuka,et al.  E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. , 2000, Journal of the National Cancer Institute.

[164]  Rui Li,et al.  Comprehensive analysis of the gene expression profiles in human gastric cancer cell lines , 2002, Oncogene.

[165]  A. Hölscher,et al.  Increased Galectin-3 Expression in Gastric Cancer: Correlations with Histopathological Subtypes, Galactosylated Antigens and Tumor Cell Proliferation , 2000, Tumor Biology.

[166]  V. Ingram,et al.  Cloning and sequencing of a cDNA encoding DNA methyltransferase of mouse cells. The carboxyl-terminal domain of the mammalian enzymes is related to bacterial restriction methyltransferases. , 1988, Journal of molecular biology.

[167]  K. Mimori,et al.  Prognostic score of gastric cancer determined by cDNA microarray. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[168]  M. Sobrinho-Simões,et al.  Expression of fully and under‐glycosylated forms of MUC1 mucin in gastric carcinoma , 1998, International journal of cancer.

[169]  R. Berardi,et al.  Molecular biology of sporadic gastric cancer: prognostic indicators and novel therapeutic approaches. , 2004, Cancer treatment reviews.

[170]  T. Tsukamoto,et al.  β‐Catenin mutations and nuclear accumulation during progression of rat stomach adenocarcinomas , 2003, Cancer science.

[171]  Doris Wedlich,et al.  The Wnt/Wg Signal Transducer β-Catenin Controls Fibronectin Expression , 1999, Molecular and Cellular Biology.

[172]  S. Hirohashi,et al.  DNA methyltransferase expression and DNA methylation of CPG islands and peri‐centromeric satellite regions in human colorectal and stomach cancers , 2001, International journal of cancer.

[173]  R. Jove,et al.  Requirement of Stat3 signaling for HGF/SF-Met mediated tumorigenesis , 2002, Oncogene.

[174]  M. Stolte,et al.  Differential p53 protein expression in stomach adenomas of gastric and intestinal phenotypes: possible sequences of p53 alteration in stomach carcinogenesis , 1996, Virchows Archiv.

[175]  N. Nomura,et al.  Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin- mediated cell-cell adhesion. , 1998, Science.

[176]  J. Segall,et al.  The cyclins and cyclin-dependent kinase inhibitors in hormonal regulation of proliferation and differentiation. , 1999, Endocrine reviews.

[177]  S. Itohara,et al.  Causal Relationship between the Loss of RUNX3 Expression and Gastric Cancer , 2002, Cell.

[178]  Kazuhiro Yoshida,et al.  Amplification of epidermal growth factor receptor (EGFR) gene and oncogenes in human gastric carcinomas , 1989, Virchows Archiv. B, Cell pathology including molecular pathology.

[179]  B. Bapat,et al.  Cross-talk between Rac1 GTPase and dysregulated Wnt signaling pathway leads to cellular redistribution of β-catenin and TCF/LEF-mediated transcriptional activation , 2004, Oncogene.

[180]  H. Höfler,et al.  Frequent somatic allelic inactivation of the E-cadherin gene in gastric carcinomas. , 1995, Journal of the National Cancer Institute.

[181]  Paul Polakis,et al.  The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors , 1999, Oncogene.

[182]  D. Fang,et al.  Mutation and methylation of hMLH1 in gastric carcinomas with microsatellite instability. , 2003, World journal of gastroenterology.

[183]  M. Sporn,et al.  Genetic changes in the transforming growth factor beta (TGF-beta) type II receptor gene in human gastric cancer cells: correlation with sensitivity to growth inhibition by TGF-beta. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[184]  S. Ramesh,et al.  Reduction in membranous expression of β-catenin and increased cytoplasmic E-cadherin expression predict poor survival in gastric cancer , 1999, British Journal of Cancer.

[185]  M Cereijido,et al.  Polarized monolayers formed by epithelial cells on a permeable and translucent support , 1978, The Journal of cell biology.

[186]  T. Tsukamoto,et al.  Stem cells and gastric cancer: Role of gastric and intestinal mixed intestinal metaplasia , 2003, Cancer science.

[187]  Il-Jin Kim,et al.  Promoter hypermethylation downregulates RUNX3 gene expression in colorectal cancer cell lines , 2004, Oncogene.

[188]  L. Villani,et al.  Characterization of four main cell types in gastric cancer: foveolar, mucopeptic, intestinal columnar and goblet cells. An histopathologic, histochemical and ultrastructural study of "early" and "advanced" tumours. , 1987, Pathology, research and practice.

[189]  H. Höfler,et al.  No Evidence for Mutations in the α- and β-Catenin Genes in Human Gastric and Breast Carcinomas , 1996 .

[190]  H. Yokozaki,et al.  Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas , 2002, The Journal of pathology.

[191]  H. Höfler,et al.  Pathology of upper gastrointestinal malignancies. , 2004, Seminars in oncology.

[192]  K. Miyazawa,et al.  Activation of c‐Met (hepatocyte growth factor receptor) in human gastric cancer tissue , 2004, Cancer science.

[193]  Y. Kodera,et al.  Methylation pattern of CDH13 gene in digestive tract cancers , 2004, British Journal of Cancer.

[194]  Chris Albanese,et al.  Gastrin-mediated activation of cyclin D1 transcription involves β-catenin and CREB pathways in gastric cancer cells , 2004, Oncogene.

[195]  P. Chambon,et al.  Gastric Mucosa Abnormalities and Tumorigenesis in Mice Lacking the pS2 Trefoil Protein , 1996, Science.

[196]  H. Lee,et al.  Epstein-Barr Virus-Positive Gastric Carcinoma Has a Distinct Protein Expression Profile in Comparison with Epstein-Barr Virus-Negative Carcinoma , 2004, Clinical Cancer Research.

[197]  P. Sorensen,et al.  Delayed early embryonic lethality following disruption of the murine cyclin A2 gene , 1999, Nature Genetics.

[198]  L. Yin,et al.  The expression of hTERT mRNA and cellular immunity in gastric cancer and precancerosis. , 2002, World journal of gastroenterology.

[199]  L. Wakefield,et al.  TGF-β signaling: positive and negative effects on tumorigenesis , 2002 .

[200]  T. Wang,et al.  Processing and proliferative effects of human progastrin in transgenic mice. , 1996, The Journal of clinical investigation.

[201]  J. Watari,et al.  Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype. , 2003, Human pathology.

[202]  J. Massagué,et al.  Smad4/DPC4 Silencing and Hyperactive Ras Jointly Disrupt Transforming Growth Factor-β Antiproliferative Responses in Colon Cancer Cells* , 1999, The Journal of Biological Chemistry.

[203]  J. Shay,et al.  Telomerase activity in gastric cancer. , 1995, Cancer research.

[204]  H. Höfler,et al.  Exon skipping in the E-cadherin gene transcript in metastatic human gastric carcinomas. , 1993, Human molecular genetics.

[205]  G. Bommer,et al.  Wnt/Beta-Catenin/Tcf Signaling: A Critical Pathway in Gastrointestinal Tumorigenesis , 2002, Digestion.

[206]  Chris Albanese,et al.  Gastrin-induced gastric adenocarcinoma growth is mediated through cyclin D1. , 2003, American journal of physiology. Gastrointestinal and liver physiology.

[207]  T. Wang,et al.  Progastrin expression predisposes mice to colon carcinomas and adenomas in response to a chemical carcinogen. , 2000, Gastroenterology.

[208]  J. Graff,et al.  Smad3 Mutant Mice Develop Metastatic Colorectal Cancer , 1998, Cell.

[209]  S N Thibodeau,et al.  Origin of microsatellite instability in gastric cancer. , 1999, The American journal of pathology.

[210]  D L Rimm,et al.  Beta- and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. , 1999, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[211]  K. Yanagisawa,et al.  Heterogeneities in the biological and biochemical functions of Smad2 and Smad4 mutants naturally occurring in human lung cancers , 2000, Oncogene.

[212]  Yusuke Nakamura,et al.  Genome-wide analysis of gene expression in intestinal-type gastric cancers using a complementary DNA microarray representing 23,040 genes. , 2002, Cancer research.

[213]  J. Fujimoto,et al.  Expression of Telomerase Catalytic Component, Telomerase Reverse Transcriptase, in Human Gastric Carcinomas , 1998, Japanese journal of cancer research : Gann.

[214]  Y Shimoyama,et al.  Expression of E- and P-cadherin in gastric carcinomas. , 1991, Cancer research.

[215]  D. Le Paslier,et al.  Activation of the human homologue of the Drosophila sina gene in apoptosis and tumor suppression. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[216]  T. Utsunomiya,et al.  Analysis of gastric cancer with cDNA microarray , 2004, Cancer Chemotherapy and Pharmacology.

[217]  D. Sacks,et al.  IQGAP1 and Calmodulin Modulate E-cadherin Function* , 1999, The Journal of Biological Chemistry.