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.
Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Embryonal/metabolism , DNA Methylation , GPI-Linked Proteins/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Neoplasm Proteins/metabolism , Nuclear Receptor Subfamily 6, Group A, Member 1/metabolism , Promoter Regions, Genetic , Receptors, Cytoplasmic and Nuclear/metabolism , Azacitidine/analogs & derivatives , Azacitidine/pharmacology , Binding Sites , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/genetics , Carcinoma, Ductal, Breast/pathology , Carcinoma, Embryonal/genetics , Carcinoma, Embryonal/pathology , Cell Movement , DNA Methylation/drug effects , DNA Modification Methylases/antagonists & inhibitors , DNA Modification Methylases/metabolism , Decitabine , Dose-Response Relationship, Drug , Embryonal Carcinoma Stem Cells/metabolism , Embryonal Carcinoma Stem Cells/pathology , Female , GPI-Linked Proteins/genetics , Gene Expression Regulation, Developmental , Gene Expression Regulation, Neoplastic , Genes, Reporter , Histone Deacetylase Inhibitors/pharmacology , Humans , Hydroxamic Acids/pharmacology , Intercellular Signaling Peptides and Proteins/genetics , Luciferases/biosynthesis , Luciferases/genetics , MCF-7 Cells , Neoplasm Invasiveness , Neoplasm Proteins/genetics , Nuclear Receptor Subfamily 6, Group A, Member 1/genetics , RNA Interference , RNA, Messenger/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Time Factors , Tissue Array Analysis , Transcription, Genetic , Transfection , Tretinoin/pharmacology , Valproic Acid/pharmacologyABSTRACT
Cripto-1 is critical for early embryonic development and, together with its ligand Nodal, has been found to be associated with the undifferentiated status of mouse and human embryonic stem cells. Like other embryonic genes, Cripto-1 performs important roles in the formation and progression of several types of human tumors, stimulating cell proliferation, migration, epithelial to mesenchymal transition, and tumor angiogenesis. Several studies have demonstrated that cell fate regulation during embryonic development and cell transformation during oncogenesis share common signaling pathways, suggesting that uncontrolled activation of embryonic signaling pathways might drive cell transformation and tumor progression in adult tissues. Here we review our current understanding of how Cripto-1 controls stem cell biology and how it integrates with other major embryonic signaling pathways. Because many cancers are thought to derive from a subpopulation of cancer stem-like cells, which may re-express embryonic genes, Cripto-1 signaling may drive tumor growth through the generation or expansion of tumor initiating cells bearing stem-like characteristics. Therefore, the Cripto-1/Nodal signaling may represent an attractive target for treatment in cancer, leading to the elimination of undifferentiated stem-like tumor initiating cells.
