Project description:Pancreatic cancer is the fourth leading cancer-related death in United States. The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. We performed array-comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort. We observed recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. High copy number gains, with log2 ratio >2.0, were observed in 4 cytobands, encoding genes such as G protein-coupled receptor 48, c-myc and gamma-catenin. By comparing the aCGH results of long survivors and short survivors, determined according to the median survival, we observed that loss of cytoband 18q22.3, encoding 5 genes, was the only alteration with significantly different frequencies. The copy number of the CPGL (Carboxypeptidase of glutamate-like) gene in cytoband 18q22.3 was found to be significantly associated with overall survival in univariate analyses (p=0.019 by log-rank test). This was subsequently assessed in the Italian cohort: 41 out of the 61 specimens carried deletion of the CPGL gene. Patients with deletion of the CPGL gene also had shorter overall survival (p=0.003 by log-rank test). Multivariate analysis of the two cohorts combined showed that loss of 18q22.3 / deletion of the CPGL gene was an independent poor prognostic factor for overall survival after adjusting for other factors which were found to impact the outcome (hazard ratio 2.72, p=0.0007). overexpression of the CPGL or its alternating splicing isoform CPGL-B in a pancreatic cancer cell lines resulted in slower proliferation of cells, G1 cell cycle arrest, and reduced migration activity. In conclusion, through aCGH analysis, we identified loss of 18q22.3 / deletion of the CPGL gene as potentially being an independent poor prognostic factor in resected pancreatic cancer. We further identified the CPGL gene as a potential tumor suppressor for pancreatic cancer cell lines. Array-comparative genomic hybridization was performed in 44 resected pancreatic cancer specimen from a Korean cohort. Genomic alteration relating to prognosis of the Korean cohort was further validated in a Italian cohort containing 61 resected pancreatic cancer specimens.

Project description:Pancreatic cancer is the fourth leading cancer-related death in United States. The clinical relevance of genomic imbalances in pancreatic cancer is uncertain. We performed array-comparative genomic hybridization (aCGH) in 44 resected pancreatic cancer specimens from a Korean cohort. We observed recurrent copy number gains were observed in chromosome 1q, 11q, 18q11.1-11.2, and 20q13.13; and losses in chromosome 2p, 9p, 10q, 14q, 15q, 18q12.2-23, 19q, 20q11.1, 21p, and 22q. High copy number gains, with log2 ratio >2.0, were observed in 4 cytobands, encoding genes such as G protein-coupled receptor 48, c-myc and gamma-catenin. By comparing the aCGH results of long survivors and short survivors, determined according to the median survival, we observed that loss of cytoband 18q22.3, encoding 5 genes, was the only alteration with significantly different frequencies. The copy number of the CPGL (Carboxypeptidase of glutamate-like) gene in cytoband 18q22.3 was found to be significantly associated with overall survival in univariate analyses (p=0.019 by log-rank test). This was subsequently assessed in the Italian cohort: 41 out of the 61 specimens carried deletion of the CPGL gene. Patients with deletion of the CPGL gene also had shorter overall survival (p=0.003 by log-rank test). Multivariate analysis of the two cohorts combined showed that loss of 18q22.3 / deletion of the CPGL gene was an independent poor prognostic factor for overall survival after adjusting for other factors which were found to impact the outcome (hazard ratio 2.72, p=0.0007). overexpression of the CPGL or its alternating splicing isoform CPGL-B in a pancreatic cancer cell lines resulted in slower proliferation of cells, G1 cell cycle arrest, and reduced migration activity. In conclusion, through aCGH analysis, we identified loss of 18q22.3 / deletion of the CPGL gene as potentially being an independent poor prognostic factor in resected pancreatic cancer. We further identified the CPGL gene as a potential tumor suppressor for pancreatic cancer cell lines.

Project description:INTRODUCTION: Neuronal activity regulated by synaptic communication exerts an important role in tumorigenesis and progression in brain tumors. Genes for soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) annotated with the function ‘vesicle’ about synaptic connectivity were identified and one of these proteins, synaptosomal-associated protein 25 (SNAP25), was found to have discrepant expression levels in neuropathies. However, the specific mechanism and prognostic value of SNAP25 during glioma progression remain unclear. METHODS: Using RNA sequencing data from The Cancer Genome Atlas (TCGA) database, the differential synaptosis-related genes between LGG and GBM were identified as highly correlated. Cox proportional hazards regression analysis and survival analysis indicated that the candidate gene SNAP25 could differentiate the outcome of low- and high-risk patients, and the Chinese Glioma Genome Atlas (CGGA) cohort was used for validation of the data set. RT-qPCR, western blot, and immunohistochemistry assays were performed to examine the expression level of SNAP25 in glioma cells and samples. Functional assays were performed to identify the effects of SNAP25 knockdown and overexpression on cell viability, migration, and invasion. Then, an immunofluorescence assay of the xenograft tissue was applied to evaluate the expression of the neuronal dendron formation marker-MAP2. Liquid chromatography-high re solution mass spectrometry (LC-MS)-based metabolomics approach was presented for identifying crucial metabolic disturbances in glioma cells. In situ mouse xenograft model was used to investigate the role of SNAP25 in vivo.RESULTS: SNAP25 was down expressed in glioma tissues and cell lines and low-level SNAP25 indicated an unfavorable prognosis of glioma patients. SNAP25 inhibited cell proliferation, migration, invasion and fostered glutamate metabolism of glioma cells, exerting a tumor suppressor role. SNAP25 overexpression expressed lower expression of MAP2, indicating poor neuronal plasticity and connectivity. SNAP25 could interact with glutaminase（GLS）and GLS knockdown could rescue the anti-tumor effect of SNAP25 in glioma cells. Moreover, upregulation of SNAP25 also decreased tumor volume and prolonged the overall survival (OS) of the xenograft mouse.CONCLUSION: SNAP25 inhibited carcinogenesis of glioma via sponging glutamate metabolism by regulating GLS expression, as well as inhibiting dendritic formation, which could be considered as a molecular target for glioma diagnosis and therapy.

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