Abstract
Distant metastasis is the primary cause of nasopharyngeal carcinoma (NPC) treatment failure while epithelial-mesenchymal transition (EMT) is the critical process of NPC invasion and metastasis. However, tumor-suppressor genes involved in the EMT and metastasis of NPC have not been explored clearly compared with the oncogenes. In the present study, the expression of pigment epithelium-derived factor (PEDF), a potent endogenous antitumor factor, was diminished in human NPC tissues and associated with clinicopathological and EMT features. The knockdown of PEDF induced EMT in lower metastatic NPC cell lines and overexpression of PEDF restored epithelial phenotype in higher metastatic NPC cell lines with typical EMT. The inhibition of PEDF mediated NPC cell spontaneous metastasis in vivo. LRP6/GSK3β/β-catenin signal pathway rather than AKT/GSK3β pathway was involved in the effects of PEDF on EMT. The expression of PEDF was directly downregulated by elevated miR-320c in NPC. In conclusion, our findings indicate for the first time that PEDF functions as tumor-suppressor gene in the occurrence of EMT and metastasis in NPC. PEDF could serve as a promising candidate for NPC diagnosis, prognosis and treatment.
MeSH terms
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Animals
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Base Sequence
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Binding Sites
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Carcinoma / genetics*
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Carcinoma / metabolism
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Carcinoma / mortality
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Carcinoma / pathology
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Case-Control Studies
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Cell Line, Tumor
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Epithelial-Mesenchymal Transition / genetics*
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Eye Proteins / genetics*
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Gene Expression Regulation, Neoplastic*
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Glycogen Synthase Kinase 3 beta / genetics*
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Glycogen Synthase Kinase 3 beta / metabolism
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Humans
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Low Density Lipoprotein Receptor-Related Protein-6 / genetics*
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Low Density Lipoprotein Receptor-Related Protein-6 / metabolism
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Lymphatic Metastasis
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Male
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Mice
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Mice, Nude
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MicroRNAs / genetics
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MicroRNAs / metabolism
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Nasopharyngeal Carcinoma
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Nasopharyngeal Neoplasms / genetics*
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Nasopharyngeal Neoplasms / metabolism
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Nasopharyngeal Neoplasms / mortality
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Nasopharyngeal Neoplasms / pathology
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Neoplasm Staging
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Neoplasm Transplantation
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Nerve Growth Factors / deficiency
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Nerve Growth Factors / genetics*
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Prognosis
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Serpins / deficiency
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Serpins / genetics*
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Signal Transduction
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beta Catenin / genetics*
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beta Catenin / metabolism
Substances
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CTNNB1 protein, human
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Eye Proteins
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LRP6 protein, human
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Low Density Lipoprotein Receptor-Related Protein-6
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MIRN320 microRNA, human
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MicroRNAs
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Nerve Growth Factors
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Serpins
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beta Catenin
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pigment epithelium-derived factor
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Glycogen Synthase Kinase 3 beta