Abstract
The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cadherins / genetics
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Cadherins / metabolism
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Cell Line, Tumor
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Down-Regulation
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Epithelial Cells / cytology
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Epithelial Cells / metabolism
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Gene Silencing
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Mesoderm / cytology
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Mesoderm / metabolism
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Mice
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Mice, Nude
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Nasopharyngeal Neoplasms / etiology
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Nasopharyngeal Neoplasms / genetics
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / pathology
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Nasopharynx / cytology*
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Nasopharynx / metabolism*
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Neoplasm Invasiveness
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Neoplasm Transplantation
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Polycomb Repressive Complex 1
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Snail Family Transcription Factors
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Transcription Factors / metabolism
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Transplantation, Heterologous
Substances
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BMI1 protein, human
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Cadherins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Repressor Proteins
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Snail Family Transcription Factors
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Transcription Factors
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Polycomb Repressive Complex 1
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Phosphatidylinositol 3-Kinases
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, mouse
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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PTEN Phosphohydrolase
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PTEN protein, human