title: Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer.
abstract: OBJECTIVE
  Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection.
  
  
  METHODS
  Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (≤7 months, N = 11) and long surviving (≥2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan-Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses.
  
  
  RESULTS
  Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3'UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC.
  
  
  CONCLUSIONS
  Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992-6001. ©2016 AACR.
authors.affiliation: Pancreatic Cancer Unit, Center for Cancer Research, NCI, Bethesda, Maryland.|Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Pancreatic Cancer Unit, Center for Cancer Research, NCI, Bethesda, Maryland.|Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Shouhui
authors.initials: S
authors.lastname: Yang
authors.affiliation: Pancreatic Cancer Unit, Center for Cancer Research, NCI, Bethesda, Maryland.|Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Schetter
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Gaedcke
authors.affiliation: Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
authors.forename: B Michael
authors.initials: BM
authors.lastname: Ghadimi
authors.affiliation: Genetics Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.affiliation: Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Harris G
authors.initials: HG
authors.lastname: Yfantis
authors.affiliation: Pathology and Laboratory Medicine, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland.
authors.forename: Dong H
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Matthias M
authors.initials: MM
authors.lastname: Gaida
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: Nader
authors.initials: N
authors.lastname: Hanna
authors.affiliation: Division of Surgical Oncology, University of Maryland School of Medicine, Baltimore, Maryland.
authors.forename: H Richard
authors.initials: HR
authors.lastname: Alexander
authors.affiliation: Pancreatic Cancer Unit, Center for Cancer Research, NCI, Bethesda, Maryland. hussainp@mail.nih.gov.|Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, Bethesda, Maryland.
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C470345:NOSTRIN protein, human; D003841:Deoxycytidine; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D000093542:Gemcitabine