Proteomic identification of differentially‐expressed genes in human gastric carcinomas

Although genetic alterations in proto‐oncogenes, tumor‐suppressor genes, cell cycle regulators, and cell growth factors have been implicated in the process of human gastric carcinogenesis, the principle carcinogenic mechanisms are not fully understood. In this study, we used a proteomic approach to search for genes that may be involved in gastric carcinogenesis and that might serve as diagnostic markers. We identified nine proteins with increased expression and 13 proteins with decreased expression in gastric carcinomas. The two most notable groups included proteins involved in mitotic checkpoint (MAD1L1 and EB1) and mitochondrial functions (CLPP, COX5A, and ECH1). This suggested that there are links between dysfunctions in these processes and gastric carcinogenesis. We also observed the differential expression of HSP27 and CYR61 proteins in gastric carcinoma, whose expression is known to be altered in other types of tumors. Furthermore, the study identified proteins whose function in gastric carcinomas was previously unsuspected and that may serve as new molecular markers for gastric carcinomas. Importantly, immunohistochemical analyses confirmed that the levels of expression of MAD1L1, HSP27, and CYR61 were altered in gastric carcinoma tissues. Therefore, our study suggested not only that the proteins identified in this study can be useful diagnostic markers but also that a proteomics‐based approach is useful for developing a more complete picture of the pathogenesis and function of gastric carcinomas.

[1]  S. Leung,et al.  Diverse proteomic alterations in gastric adenocarcinoma , 2004, Proteomics.

[2]  M. Oshimura,et al.  Expression of RUNX3 protein in human gastric mucosa, intestinal metaplasia and carcinoma , 2004, European journal of clinical investigation.

[3]  Jun Yu,et al.  Proteome analysis of gastric cancer metastasis by two-dimensional gel electrophoresis and matrix assisted laser desorption/ionization-mass spectrometry for identification of metastasis-related proteins. , 2004, Journal of proteome research.

[4]  Jian-zhong Zhang,et al.  Identification of tumor markers using two-dimensional electrophoresis in gastric carcinoma. , 2004, World journal of gastroenterology.

[5]  Gong Yang,et al.  Activation of Antioxidant Pathways in Ras-Mediated Oncogenic Transformation of Human Surface Ovarian Epithelial Cells Revealed by Functional Proteomics and Mass Spectrometry , 2004, Cancer Research.

[6]  Carl W. Miller,et al.  Cyr61 suppresses the growth of non-small-cell lung cancer cells via the β-catenin–c-myc–p53 pathway , 2004, Oncogene.

[7]  Kosei Ito,et al.  Growth regulation of gastric epithelial cells by Runx3 , 2004, Oncogene.

[8]  Hirofumi Nakayama,et al.  Search for new biomarkers of gastric cancer through serial analysis of gene expression and its clinical implications , 2004, Cancer science.

[9]  Carlo Rago,et al.  Inactivation of hCDC4 can cause chromosomal instability , 2004, Nature.

[10]  H. Christian,et al.  Expression, subcellular localization and phosphorylation status of annexins 1 and 5 in human pituitary adenomas and a growth hormone‐secreting carcinoma , 2004, Clinical endocrinology.

[11]  R. Green,et al.  Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC , 2003, The Journal of cell biology.

[12]  R. Nishigaki,et al.  Searching for genes involved in arteriosclerosis: proteomic analysis of cultured human umbilical vein endothelial cells undergoing replicative senescence. , 2003, Cell structure and function.

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

[14]  Richard Weindruch,et al.  A design and statistical perspective on microarray gene expression studies in nutrition: the need for playful creativity and scientific hard-mindedness. , 2003, Nutrition.

[15]  M. Oshimura,et al.  Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. , 2003, Biochemical and biophysical research communications.

[16]  J. Cigudosa,et al.  Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. , 2003, Cancer research.

[17]  Martin A. Nowak,et al.  The significance of unstable chromosomes in colorectal cancer , 2003, Nature Reviews Cancer.

[18]  N. Myong,et al.  The proteomics approach to find biomarkers in gastric cancer. , 2003, Journal of Korean medical science.

[19]  T. Toda,et al.  Proteome analysis of Epstein-Barr virus-transformed B-lymphoblasts and the proteome database. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[20]  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.

[21]  Martin A. Nowak,et al.  The role of chromosomal instability in tumor initiation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[22]  R. Lupu,et al.  Cyr61 promotes breast tumorigenesis and cancer progression , 2002, Oncogene.

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

[24]  K. Jeang,et al.  Characterization of Regions in hsMAD1 Needed for Binding hsMAD2 , 2002, The Journal of Biological Chemistry.

[25]  Chang-Won Lee,et al.  Proteome analysis of human stomach tissue: Separation of soluble proteins by two‐dimensional polyacrylamide gel electrophoresis and identification by mass spectrometry , 2002, Electrophoresis.

[26]  A. Papavassiliou,et al.  Expression of the 27-kDa heat shock protein (HSP27) in gastric carcinomas and adjacent normal, metaplastic, and dysplastic gastric mucosa, and its prognostic significance , 2002, Journal of Cancer Research and Clinical Oncology.

[27]  R. Nishigaki,et al.  An extra human chromosome 21 reduces mlc-2a expression in chimeric mice and Down syndrome. , 2002, Biochemical and biophysical research communications.

[28]  Sharon L R Kardia,et al.  Proteomic analysis of lung adenocarcinoma: identification of a highly expressed set of proteins in tumors. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[29]  K. Jeang,et al.  Expression of mitotic spindle checkpoint protein hsMAD1 correlates with cellular proliferation and is activated by a gain-of-function p53 mutant. , 2002, Cancer research.

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

[31]  M. Monden,et al.  Human stomach-specific gene, CA11, is down-regulated in gastric cancer. , 2001, International journal of oncology.

[32]  J. Celis,et al.  Characterization of the differential protein expression associated with thermoresistance in human gastric carcinoma cell lines , 2001, Electrophoresis.

[33]  Carl W. Miller,et al.  Mutations in the mitotic check point gene, MAD1L1, in human cancers , 2001, Oncogene.

[34]  S. Takeno,et al.  Analysis of the Survival Period in Resectable Stage IV Gastric Cancer , 2001, Annals of Surgical Oncology.

[35]  W. Gerald,et al.  MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells , 2001, Nature.

[36]  Y. Yoshikawa,et al.  Isolation of Two Novel Genes, Down‐regulated in Gastric Cancer , 2000, Japanese journal of cancer research : Gann.

[37]  H. Hosoya,et al.  Small heat shock protein 27 (HSP27) associates with tubulin/microtubules in HeLa cells. , 2000, Biochemical and biophysical research communications.

[38]  Barbara E. Bierer,et al.  The APC-associated protein EB1 associates with components of the dynactin complex and cytoplasmic dynein intermediate chain , 1999, Current Biology.

[39]  D. Pellman,et al.  The adenomatous polyposis coli-binding protein EB1 is associated with cytoplasmic and spindle microtubules. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M. Tagawa,et al.  Increased Hepatic Nicotinamide N‐Methyltransferase Activity as a Marker of Cancer Cachexia in Mice Bearing Colon 26 Adenocarcinoma , 1998, Japanese journal of cancer research : Gann.

[41]  T. V. Kolesnikova,et al.  CYR61, a product of a growth factor-inducible immediate early gene, promotes angiogenesis and tumor growth. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Kuan-Teh Jeang,et al.  Human T Cell Leukemia Virus Type 1 Oncoprotein Tax Targets the Human Mitotic Checkpoint Protein MAD1 , 1998, Cell.

[43]  Bert Vogelstein,et al.  Mutations of mitotic checkpoint genes in human cancers , 1998, Nature.

[44]  T. Toda,et al.  TMIG‐2DPAGE: A new concept of two‐dimensional gel protein database for research on aging , 1998, Electrophoresis.

[45]  H. Wieand,et al.  Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors. , 1989, Cancer research.

[46]  M. De la Fuente,et al.  Enzymes of mannose metabolism in murine and human lymphocytic leukaemia. , 1988, British Journal of Cancer.

[47]  S. Hsu,et al.  Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. , 1981, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[48]  M. Grzmil,et al.  Up-regulated expression of the MAT-8 gene in prostate cancer and its siRNA-mediated inhibition of expression induces a decrease in proliferation of human prostate carcinoma cells. , 2004, International journal of oncology.

[49]  Keizo Sugimachi,et al.  Analysis of the gene-expression profile regarding the progression of human gastric carcinoma. , 2002, Surgery.

[50]  M. Hayakari,et al.  Decreased expression of the peroxisomal bifunctional enzyme and carbonyl reductase in human hepatocellular carcinomas , 1999, Journal of Cancer Research and Clinical Oncology.

[51]  P. Laurén.  Histogenesis of intestinal and diffuse types of gastric carcinoma. , 1991, Scandinavian journal of gastroenterology. Supplement.