title: Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia.
abstract: Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. The Tff1 knockout (KO) mouse model develops gastric lesions that include low-grade dysplasia (LGD), high-grade dysplasia (HGD), and adenocarcinomas. In this study, we used Affymetrix microarrays gene expression platforms for analysis of molecular signatures in the mouse stomach [Tff1-KO (LGD) and Tff1 wild-type (normal)] and human gastric cancer tissues and their adjacent normal tissue samples. Combined integrated bioinformatics analysis of mouse and human datasets indicated that 172 genes were consistently deregulated in both human gastric cancer samples and Tff1-KO LGD lesions (P < .05). Using Ingenuity pathway analysis, these genes mapped to important transcription networks that include MYC, STAT3, β-catenin, RELA, NFATC2, HIF1A, and ETS1 in both human and mouse. Further analysis demonstrated activation of FOXM1 and inhibition of TP53 transcription networks in human gastric cancers but not in Tff1-KO LGD lesions. Using real-time RT-PCR, we validated the deregulated expression of several genes (VCAM1, BGN, CLDN2, COL1A1, COL1A2, COL3A1, EpCAM, IFITM1, MMP9, MMP12, MMP14, PDGFRB, PLAU, and TIMP1) that map to altered transcription networks in both mouse and human gastric neoplasia. Our study demonstrates significant similarities in deregulated transcription networks in human gastric cancer and gastric tumorigenesis in the Tff1-KO mouse model. The data also suggest that activation of MYC, STAT3, RELA, and β-catenin transcription networks could be an early molecular step in gastric carcinogenesis.
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37232.|Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37232.|Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Soutto
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Bushra
authors.initials: B
authors.lastname: Rahman
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Muhammad W
authors.initials: MW
authors.lastname: Fazili
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: DunFa
authors.initials: D
authors.lastname: Peng
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Gastroenterology, Hepatology, & Nutrition, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Maria
authors.initials: M
authors.lastname: Blanca Piazuelo
authors.affiliation: Center of Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232.
authors.forename: Heidi
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232.
authors.forename: M
authors.initials: M
authors.lastname: Kay Washington
authors.affiliation: Center of Quantitative Sciences, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, 37232.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shyr
authors.affiliation: Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, 37232.|Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, 37232.|Division of Surgical Oncology, Vanderbilt University Medical Center, Nashville, TN, 37232.
authors.forename: Wael
authors.identifier: 0000-0003-2101-6098
authors.initials: W
authors.lastname: El-Rifai
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D004195:Disease Models, Animal; D005753:Gastric Mucosa / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D053263:Gene Regulatory Networks / Q000235:genetics*; D006801:Humans; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D013270:Stomach / Q000737:chemistry*; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*