ABSTRACT
BACKGROUND: Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase and often aberrantly expressed in human cancers. However, Syk expression pattern has not yet been investigated in nasopharyngeal carcinoma (NPC). METHODS: Samples of 223 NPC tissues were immunohistochemically stained for Syk expression and survival analysis was then performed. Interaction and co-localization of Syk with Epstein-Barr virus encoded latent membrane protein 2A (LMP2A) was explored. RESULTS: High expression of Syk was detected in 24% of NPC cases, and correlated significantly with T classification, local recurrence, a lower 5-year survival rate, and a lower 5-year disease-free survival (DFS) rate. Syk expression was a significant, independent prognosis predictor for patients with NPC. LMP2A induced Syk expression in NPC and LMP2A high expression correlated with Syk high expression in NPC clinical samples. CONCLUSION: High expression of Syk, which results partly from LMP2A expression in NPC, is associated with tumor recurrence and poor prognosis of patients with NPC.
Subject(s)
Gene Expression Regulation, Neoplastic , Intracellular Signaling Peptides and Proteins/metabolism , Nasopharyngeal Neoplasms/mortality , Nasopharyngeal Neoplasms/pathology , Protein-Tyrosine Kinases/metabolism , Viral Matrix Proteins/metabolism , Adult , Analysis of Variance , Biopsy, Needle , Blotting, Western , Carcinoma , Cohort Studies , Female , Fluorescent Antibody Technique , Humans , Immunohistochemistry , Immunoprecipitation , In Situ Hybridization , Intracellular Signaling Peptides and Proteins/genetics , Kaplan-Meier Estimate , Male , Middle Aged , Multivariate Analysis , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/radiotherapy , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Predictive Value of Tests , Prognosis , Proportional Hazards Models , Protein-Tyrosine Kinases/genetics , Retrospective Studies , Survival Rate , Syk Kinase , Tissue Embedding , Viral Matrix Proteins/geneticsABSTRACT
Expression of caveolin-1 (Cav-1) and extracellular matrix metalloproteinase inducer (EMMPRIN/CD147) and their prognostic significance were analyzed in archive NPC samples. Cav-1 and CD147 were overexpressed in 49.48% (96/194) and 59.39% (117/197) of NPC, respectively. Both Cav-1 and CD147 expression levels correlated significantly with metastasis (p = 0.025 and 0.017, respectively) and a lower 5-year survival rate (p = 0.02 and 0.0009, respectively). In addition, Cav-1 expression levels correlated significantly with local recurrence (p = 0.038). Multivariate Cox regression analysis indicated that combination of high Cav-1 and CD147 expression was a significant, independent prognosis predictor in patients with NPC (HR = 2.135; p = 0.006). Functional studies revealed that overexpression of Cav-1 promoted secretion of MMP-3 and MMP-11 (active) proteins, as well as an increase in the migratory ability of CNE1 and CNE2 cells, while siRNA-mediated silencing of Cav-1 or CD147 led to reduced levels of MMP-3 and MMP-11(active) secretion, and reduced migration capacity of CNE1 and CNE2 cells. We observed a positive correlation between Cav-1 and CD147 expression in NPC (rho = 0.330, p = 0.000), CD147 protein levels were upregulated in Cav-1 overexpressing CNE1 and CNE2 cells, whereas siRNA-mediated silencing of Cav-1 led to the downregulation of CD147 expression. Our results indicate that Cav-1 and CD147 overexpression predict poor NPC prognosis and enhanced tumor cell migration, which is associated with MMP-3 and MMP-11 (active) secretion.
Subject(s)
Basigin/metabolism , Caveolin 1/metabolism , Cell Movement , Nasopharyngeal Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Up-Regulation/physiology , Adolescent , Adult , Aged , Aged, 80 and over , Basigin/genetics , Caveolin 1/antagonists & inhibitors , Caveolin 1/genetics , Female , Humans , Immunoblotting , Immunoenzyme Techniques , Lymphatic Metastasis , Male , Matrix Metalloproteinase 11/metabolism , Matrix Metalloproteinase 3/metabolism , Middle Aged , Nasopharyngeal Neoplasms/pathology , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Rate , Tissue Array Analysis , Tumor Cells, Cultured , Young AdultABSTRACT
Functional studies to identify the potential role of a chromosome 3p14-21 gene, protein tyrosine phosphatase receptor type G (PTPRG), were performed. PTPRG was identified as a candidate tumor suppressor gene (TSG) in nasopharyngeal carcinoma (NPC) by differential gene profiling of tumorigenic and nontumorigenic NPC chromosome 3 microcell hybrids (MCH). Down-regulation of this gene was found in tumor segregants when compared with their corresponding tumor-suppressive MCHs, as well as in NPC cell lines and tumor biopsies. Promoter hypermethylation and loss of heterozygosity were found to be important mechanisms contributing to PTPRG silencing. PTPRG overexpression in NPC cell lines induces growth suppression and reduced anchorage-independent growth in vitro. This is the first study to use a tetracycline-responsive vector expression system to study PTPRG stable transfectants. Results indicate its ability to induce significant tumor growth suppression in nude mice under conditions activating transgene expression. These studies now provide functional evidence indicating critical interactions of PTPRG in the extracellular matrix milieu induce cell arrest and changes in cell cycle status. This is associated with inhibition of pRB phosphorylation through down-regulation of cyclin D1. These novel findings enhance our current understanding of how PTPRG may contribute to tumorigenesis.
