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Metabolites of Purine Nucleoside Phosphorylase (NP) in Serum Have the Potential to Delineate Pancreatic Adenocarcinoma

By Shaiju K. Vareed, Vadiraja B. Bhat, Christopher Thompson, Vihas T. Vasu, Damian Fermin, Hyungwon Choi, Chad J. Creighton, Sitaram Gayatri, Ling Lan, Nagireddy Putluri, Gagan Singh Thangjam, Punit Kaur, Mohsen Shabahang, Judith G. Giri, Alexey I. Nesvizhskii, Alexander A. A. Asea, Anil G. Cashikar, Arundhati Rao, James McLoughlin and Arun Sreekumar

Abstract

Pancreatic Adenocarcinoma (PDAC), the fourth highest cause of cancer related deaths in the United States, has the most aggressive presentation resulting in a very short median survival time for the affected patients. Early detection of PDAC is confounded by lack of specific markers that has motivated the use of high throughput molecular approaches to delineate potential biomarkers. To pursue identification of a distinct marker, this study profiled the secretory proteome in 16 PDAC, 2 carcinoma in situ (CIS) and 7 benign patients using label-free mass spectrometry coupled to 1D-SDS-PAGE and Strong Cation-Exchange Chromatography (SCX). A total of 431 proteins were detected of which 56 were found to be significantly elevated in PDAC. Included in this differential set were Parkinson disease autosomal recessive, early onset 7 (PARK 7) and Alpha Synuclein (aSyn), both of which are known to be pathognomonic to Parkinson's disease as well as metabolic enzymes like Purine Nucleoside Phosphorylase (NP) which has been exploited as therapeutic target in cancers. Tissue Microarray analysis confirmed higher expression of aSyn and NP in ductal epithelia of pancreatic tumors compared to benign ducts. Furthermore, extent of both aSyn and NP staining positively correlated with tumor stage and perineural invasion while their intensity of staining correlated with the existence of metastatic lesions in the PDAC tissues. From the biomarker perspective, NP protein levels were higher in PDAC sera and furthermore serum levels of its downstream metabolites guanosine and adenosine were able to distinguish PDAC from benign in an unsupervised hierarchical classification model. Overall, this study for the first time describes elevated levels of aSyn in PDAC as well as highlights the potential of evaluating NP protein expression and levels of its downstream metabolites to develop a multiplex panel for non-invasive detection of PDAC

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3063153
Provided by: PubMed Central

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Citations

  1. (2002). A direct approach to false discovery rates.
  2. (2006). Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma.
  3. (1993). Acute myeloid leukemia: correlation between purine metabolism enzyme activities and membrane immunophenotype.
  4. (1997). Alpha-synuclein in Lewy bodies.
  5. (2003). alphaSynuclein locus triplication causes Parkinson’s disease.
  6. an oncogene and causative gene for familial Parkinson’s disease, is essential for SV40 transformation in mouse fibroblasts through up-regulation of c-Myc.
  7. (2003). Analysis of nitrated proteins by nitrotyrosine-specific affinity probes and mass spectrometry.
  8. (2009). Analysis of the pancreatic tumor progression by a quantitative proteomic approach and immunhistochemical validation.
  9. (2010). Application of a time-varying covariate model to the analysis of CA 19-9 as serum biomarker in patients with advanced pancreatic cancer.
  10. (2006). Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach.
  11. (2003). Breast cancer-specific gene 1 interacts with the mitotic checkpoint kinase BubR1.
  12. (1998). CA 19-9 in pancreatic cancer.
  13. (2000). Can we screen high-risk individuals to detect early pancreatic carcinoma?
  14. (2009). Cancer statistics,
  15. (2009). Clinical significance of serum tumour M2-PK and CA19-9 detection in the diagnosis of cholangiocarcinoma.
  16. (1998). Cluster analysis and display of genome-wide expression patterns.
  17. (2005). Comparative plasma proteome analysis of lymphoma-bearing SJL mice.
  18. (2007). Comparative time-dependent analysis of potential inflammation biomarkers in lymphoma-bearing SJL mice.
  19. (2007). Comparison of pancreas juice proteins from cancer versus pancreatitis using quantitative proteomic analysis.
  20. (2004). Comprehensive proteomic analysis of human pancreatic juice.
  21. (2005). Comprehensive proteomics in yeast using chromatographic fractionation, gas phase fractionation, protein gel electrophoresis, and isoelectric focusing.
  22. (2008). Core Team
  23. DJ-1 modulates the p38 mitogen-activated protein kinase pathway through physical interaction with apoptosis signal-regulating kinase 1.
  24. (2003). DJ1(PARK7), a novel gene for autosomal recessive, early onset parkinsonism.
  25. (2005). Early detection markers in Pancreas Cancer.
  26. (2002). Early detection of pancreatic carcinoma.
  27. (1998). Effects of a novel purine nucleoside phosphorylase inhibitor, BCX-34, on activation and proliferation of normal human lymphoid cells.
  28. (2006). Efficient fractionation and improved protein identification by peptide OFFGEL electrophoresis.
  29. Elevated level of anterior gradient-2 in pancreatic juice from patients with pre-malignant pancreatic neoplasia.
  30. (2007). Evaluation of the SELDITOF MS technique for protein profiling of pancreatic islets exposed to glucose and oleate.
  31. Expression of alpha-, beta- and gamma-synuclein in colorectal cancer, and potential clinical significance in progression of the disease.
  32. (2009). Expression of gammasynuclein in colorectal cancer tissues and its role on colorectal cancer cell line HCT116.
  33. (1992). Fernandez-del Castillo C
  34. (2007). Gammasynuclein and the progression of cancer.
  35. (2008). In vivo alpha-synuclein overexpression in rodents: a useful model of Parkinson’s disease?
  36. (2005). Interpretation of shotgun proteomic data: the protein inference problem.
  37. (2004). Java Treeview–extensible visualization of microarray data.
  38. (2002). Management of pancreatic mass accompanying chronic pancreatitis.
  39. (1996). Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23.
  40. (1996). Mass spectrometric sequencing of proteins silver-stained polyacrylamide gels.
  41. (1997). Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease.
  42. (1997). Mutations in purine nucleoside phosphorylase deficiency.
  43. (2007). N-linked glycosylation profiling of pancreatic cancer serum using capillary liquid phase separation coupled with mass spectrometric analysis.
  44. (1975). Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity.
  45. (2000). Omura GA
  46. (2009). Pancreatic cancer: proteomic approaches to a challenging disease.
  47. (1984). Pancreatic juice protein associated with chronic pancreatitis and adenocarcinoma of the pancreas.
  48. (2001). Park7, a novel locus for autosomal recessive early-onset parkinsonism, on chromosome 1p36.
  49. (2006). Parkinson’s disease alpha-synuclein transgenic mice develop neuronal mitochondrial degeneration and cell death.
  50. Parkinson’s disease-related protein, alpha-synuclein, in malignant melanoma.
  51. Pathology analysis reveals that dysplastic pancreatic ductal lesions are frequent in patients with hereditary pancreatitis.
  52. (2007). Phosphoproteomic analysis of neuronal cell death by glutamate-induced oxidative stress.
  53. (2007). Plasma proteomics of pancreatic cancer patients by multi-dimensional liquid chromatography and two-dimensional difference gel electrophoresis (2D-DIGE): upregulation of leucine-rich alpha-2-glycoprotein in pancreatic cancer.
  54. (2004). Plasma purine nucleoside phosphorylase in cancer patients.
  55. Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes–a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies.
  56. Production of a monoclonal antibody, against human alpha-synuclein, in a subpopulation of C57BL/6J mice, presenting a deletion of the alpha-synuclein locus.
  57. (2003). Profiling core proteomes of human cell lines by one-dimensional PAGE and liquid chromatography-tandem mass spectrometry.
  58. (2006). Prognostic and therapeutic significance of carbohydrate antigen 19-9 as tumor marker in patients with pancreatic cancer.
  59. (2009). Prognostic value of serum tumor antigen CA19-9 after curative resection of colorectal cancer.
  60. (2007). Protein profiling of microdissected pancreas carcinoma and identification of HSP27 as a potential serum marker.
  61. (2008). Proteomic analysis identifies MMP-9, DJ-1 and A1BG as overexpressed proteins in pancreatic juice from pancreatic ductal adenocarcinoma patients.
  62. (2005). Proteomic analysis of chronic pancreatitis and pancreatic adenocarcinoma.
  63. (2009). Proteomic analysis of pancreatic ductal adenocarcinoma compared with normal adjacent pancreatic tissue and pancreatic benign cystadenoma.
  64. (2008). Proteomic analysis to identify biomarker proteins in pancreatic ductal adenocarcinoma.
  65. (2009). Proteomic and tissue array profiling identifies elevated hypoxia-regulated proteins in pancreatic ductal adenocarcinoma.
  66. (2005). Proteomic profiling of pancreatic cancer for biomarker discovery.
  67. (2006). Quantitative proteomic profiling of pancreatic cancer juice.
  68. Quantitative proteomic profiling of prostate cancer reveals a role for miR-128 in prostate cancer.
  69. (2007). Serum proteomicbased analysis of pancreatic carcinoma for the identification of potential cancer biomarkers.
  70. (1999). Stimulation of breast cancer invasion and metastasis by synuclein gamma.
  71. (2009). Synuclein-gamma (SNCG) may be a novel prognostic biomarker in uterine papillary serous carcinoma.
  72. (2009). Synucleingamma is closely involved in perineural invasion and distant metastasis in mouse models and is a novel prognostic factor in pancreatic cancer.
  73. The familial Parkinson’s disease gene DJ-1 (PARK7) is expressed in red cells and plays a role in protection against oxidative damage.
  74. (2005). The Parkinson’s disease-associated DJ-1 protein is a transcriptional co-activator that protects against neuronal apoptosis.
  75. (2008). Transient marked elevation of serum CA 19-9 levels in a patient with acute cholangitis and biliary stent.
  76. (2001). Two novel mutations in a purine nucleoside phosphorylase (PNP)-deficient patient.
  77. (2004). Undetectable preoperative levels of serum CA 19-9 correlate with improved survival for patients with resectable pancreatic adenocarcinoma.
  78. Zho uL,LuZ,Yan gA,D e ngR ,Ma iC,e ta l .( 2 0 07 )Co m pa ra t iv epr o te o mi ca nal ys is of human pancreatic juice: methodological study.