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Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial-Mesenchymal Transition Regulated by miR-200 in Breast Cancer Cells
- Source :
- Cancer Research. 71:3400-3409
- Publication Year :
- 2011
- Publisher :
- American Association for Cancer Research (AACR), 2011.
-
Abstract
- Phosphoglucose isomerase/autocrine motility factor (PGI/AMF) plays an important role in glycolysis and gluconeogenesis and is associated with invasion and metastasis of cancer cells. We have previously shown its role in the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells, which led to increased aggressiveness; however, the molecular mechanism by which PGI/AMF regulates EMT is not known. Here we show, for the first time, that PGI/AMF overexpression led to an increase in the DNA-binding activity of NF-κB, which, in turn, led to increased expression of ZEB1/ZEB2. The microRNA-200s (miR-200s) miR-200a, miR-200b, and miR-200c are known to negatively regulate the expression of ZEB1/ZEB2, and we found that the expression of miR-200s was lost in PGI/AMF overexpressing MCF-10A cells and in highly invasive MDA-MB-231 cells, which was consistent with increased expression of ZEB1/ZEB2. Moreover, silencing of PGI/AMF expression in MDA-MB-231 cells led to overexpression of miR-200s, which was associated with reversal of EMT phenotype (i.e., mesenchymal-epithelial transition), and these findings were consistent with alterations in the relative expression of epithelial (E-cadherin) and mesenchymal (vimentin, ZEB1, ZEB2) markers and decreased aggressiveness as judged by clonogenic, motility, and invasion assays. Moreover, either reexpression of miR-200 or silencing of PGI/AMF suppressed pulmonary metastases of MDA-MB-231 cells in vivo, and anti-miR-200 treatment in vivo resulted in increased metastases. Collectively, these results suggest a role of miR-200s in PGI/AMF-induced EMT and thus approaches for upregulation of miR-200s could be a novel therapeutic strategy for the treatment of highly invasive breast cancer. Cancer Res; 71(9); 3400–9. ©2011 AACR.
- Subjects :
- Cancer Research
medicine.medical_specialty
Autocrine Motility Factor
Epithelial-Mesenchymal Transition
Lung Neoplasms
Transcription, Genetic
Motility
Breast Neoplasms
Vimentin
Biology
Transfection
Article
Metastasis
Downregulation and upregulation
Cell Movement
Cell Line, Tumor
Internal medicine
medicine
Humans
Gene silencing
Epithelial–mesenchymal transition
Zinc Finger E-box Binding Homeobox 2
Homeodomain Proteins
Glucose-6-Phosphate Isomerase
NF-kappa B
Zinc Finger E-box-Binding Homeobox 1
medicine.disease
Up-Regulation
Repressor Proteins
MicroRNAs
Endocrinology
Oncology
Cancer cell
Cancer research
biology.protein
Female
Transcription Factors
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....833809a315ddca2d318820f00ed2f479