TY - JOUR
T1 - Integrated expression analysis identifies transcription networks in mouse and human gastric neoplasia
AU - Chen, Zheng
AU - Soutto, Mohammed
AU - Rahman, Bushra
AU - Fazili, Muhammad W.
AU - Peng, Dun Fa
AU - Blanca Piazuelo, Maria
AU - Chen, Heidi
AU - Kay Washington, M.
AU - Shyr, Yu
AU - El-Rifai, Wael
N1 - Funding Information:
This study was supported by a Research Career Scientist award (1IK6BX003787) and merit award (I01BX001179) from the U.S. Department of Veterans affairs (W. El-Rifai), and grants from the U.S. National Institutes of Health (R01CA93999), Vanderbilt SPORE in Gastrointestinal Cancer (P50 CA95103), Vanderbilt-Ingram Cancer Center (P30 CA68485), and the Vanderbilt Digestive Disease Research Center (DK058404). The contents of this work are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Veterans Affairs, National Institutes of Health, or Vanderbilt University Medical Center. No potential conflicts of interest were disclosed Summarized data: Zheng Chen Prepared figures: Zheng Chen Wrote a draft: Zheng Chen In vivo experiments: Mohammed Soutto Interpretation of data: Mohammed Soutto, Dunfa Peng Assisted in validation of gene expression: Bushra Rahman, Muhammad W. Fazili Preparation of samples: Dunfa Peng Histopathology analysis of mouse and human tissues: Maria Blanca Piazuelo, M. Kay Washington Analyzed and interpreted microarray data: Heidi Chen, Wael El-Rifai Assisted in data analysis and interpretation: Yu Shyr Study concept and design: Wael El-Rifai Study supervision: Wael El-Rifai Experimental troubleshooting: Wael El-Rifai Drafting of the manuscript: Wael El-Rifai Critical revision of the manuscript: Wael El-Rifai
PY - 2017/7
Y1 - 2017/7
N2 - 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.
AB - 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.
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U2 - 10.1002/gcc.22456
DO - 10.1002/gcc.22456
M3 - Article
C2 - 28281307
AN - SCOPUS:85017356327
VL - 56
SP - 535
EP - 547
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
SN - 1045-2257
IS - 7
ER -