Abstract
Tissue hypoxia induces reprogramming of cell metabolism and may result in normal cell transformation and cancer progression. Hypoxia-inducible factor 1-alpha (HIF-1α), the key transcription factor, plays an important role in gastric cancer development and progression. This study aimed to investigate the underlying regulatory signaling pathway in gastric cancer using gastric cancer tissue specimens. The integration of gene expression profile and transcriptional regulatory element database (TRED) was pursued to identify HIF-1α ↔ NFκB1 → BRCA1 → STAT3 ← STAT1 gene pathways and their regulated genes. The data showed that there were 82 differentially expressed genes that could be regulated by these five transcription factors in gastric cancer tissues and these genes formed 95 regulation modes, among which seven genes (MMP1, TIMP1, TLR2, FCGR3A, IRF1, FAS, and TFF3) were hub molecules that are regulated at least by two of these five transcription factors simultaneously and were associated with hypoxia, inflammation, and immune disorder. Real-Time PCR and western blot showed increasing of HIF-1α in mRNA and protein levels as well as TIMP1, TFF3 in mRNA levels in gastric cancer tissues. The data are the first study to demonstrate HIF-1α-regulated transcription factors and their corresponding network genes in gastric cancer. Further study with a larger sample size and more functional experiments is needed to confirm these data and then translate into clinical biomarker discovery and treatment strategy for gastric cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Gene Expression Regulation, Neoplastic / genetics
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Gene Expression Regulation, Neoplastic / physiology
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Genes, Regulator / genetics
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Genes, Regulator / physiology*
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Interferon Regulatory Factor-1 / genetics
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Interferon Regulatory Factor-1 / metabolism
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Matrix Metalloproteinase 1 / genetics
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Matrix Metalloproteinase 1 / metabolism
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Peptides / genetics
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Peptides / metabolism
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Receptors, IgG / genetics
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Receptors, IgG / metabolism
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Stomach Neoplasms / genetics
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Stomach Neoplasms / metabolism*
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Tissue Inhibitor of Metalloproteinase-1 / genetics
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Tissue Inhibitor of Metalloproteinase-1 / metabolism
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 2 / metabolism
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Trefoil Factor-3
Substances
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FCGR3A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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IRF1 protein, human
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Interferon Regulatory Factor-1
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Peptides
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Receptors, IgG
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TFF3 protein, human
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TIMP1 protein, human
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TLR2 protein, human
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Tissue Inhibitor of Metalloproteinase-1
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Toll-Like Receptor 2
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Trefoil Factor-3
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MMP1 protein, human
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Matrix Metalloproteinase 1
Grants and funding
This work was supported in part by grants from National Natural Science Foundation of China (#81320108025 and #81271897), Specialized Research Fund for the Doctoral Program of Higher Education of China (#20110061120093), China Postdoctoral Science Foundation (#20110491311 and #2012T50285), Foundation of Jilin Provincial Health Department (#2011Z049), Foundation of Jilin Province Science and Technology Department (#20130522013JH and #20140414048GH) and the Norman Bethune Program of Jilin University (#2012219). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.