Abstract
Human Cripto-1 (CR-1) plays an important role in regulating embryonic development while also regulating various stages of tumor progression. However, mechanisms that regulate CR-1 expression during embryogenesis and tumorigenesis are still not well defined. In the present study, we investigated the effects of two nuclear receptors, liver receptor homolog (LRH)-1 and germ cell nuclear factor receptor (GCNF) and epigenetic modifications on CR-1 gene expression in NTERA-2 human embryonal carcinoma cells and in breast cancer cells. CR-1 expression in NTERA-2 cells was positively regulated by LRH-1 through direct binding to a DR0 element within the CR-1 promoter, while GCNF strongly suppressed CR-1 expression in these cells. In addition, the CR-1 promoter was unmethylated in NTERA-2 cells, while T47D, ZR75-1, and MCF7 breast cancer cells showed high levels of CR-1 promoter methylation and low CR-1 mRNA and protein expression. Treatment of breast cancer cells with a demethylating agent and histone deacetylase inhibitors reduced methylation of the CR-1 promoter and reactivated CR-1 mRNA and protein expression in these cells, promoting migration and invasion of breast cancer cells. Analysis of a breast cancer tissue array revealed that CR-1 was highly expressed in the majority of human breast tumors, suggesting that CR-1 expression in breast cancer cell lines might not be representative of in vivo expression. Collectively, these findings offer some insight into the transcriptional regulation of CR-1 gene expression and its critical role in the pathogenesis of human cancer.
Copyright © 2012 Wiley Periodicals, Inc.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Azacitidine / analogs & derivatives
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Azacitidine / pharmacology
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Binding Sites
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology
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Carcinoma, Ductal, Breast / genetics
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Carcinoma, Ductal, Breast / metabolism*
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Carcinoma, Ductal, Breast / pathology
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Carcinoma, Embryonal / genetics
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Carcinoma, Embryonal / metabolism*
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Carcinoma, Embryonal / pathology
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Cell Movement
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DNA Methylation* / drug effects
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DNA Modification Methylases / antagonists & inhibitors
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DNA Modification Methylases / metabolism
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Decitabine
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Dose-Response Relationship, Drug
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Embryonal Carcinoma Stem Cells / metabolism
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Embryonal Carcinoma Stem Cells / pathology
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Female
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / metabolism*
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Gene Expression Regulation, Developmental
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Gene Expression Regulation, Neoplastic
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Genes, Reporter
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Histone Deacetylase Inhibitors / pharmacology
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Humans
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Hydroxamic Acids / pharmacology
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Luciferases / biosynthesis
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Luciferases / genetics
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MCF-7 Cells
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Neoplasm Invasiveness
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Receptor Subfamily 6, Group A, Member 1 / genetics
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Nuclear Receptor Subfamily 6, Group A, Member 1 / metabolism*
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Promoter Regions, Genetic*
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RNA Interference
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RNA, Messenger / metabolism
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Time Factors
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Tissue Array Analysis
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Transcription, Genetic
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Transfection
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Tretinoin / pharmacology
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Valproic Acid / pharmacology
Substances
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GPI-Linked Proteins
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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Intercellular Signaling Peptides and Proteins
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NR5A2 protein, human
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NR6A1 protein, human
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Neoplasm Proteins
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Nuclear Receptor Subfamily 6, Group A, Member 1
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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TDGF1 protein, human
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trichostatin A
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Tretinoin
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Valproic Acid
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Decitabine
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Luciferases
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DNA Modification Methylases
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Azacitidine