title: Identification of deregulation of apoptosis and cell cycle in neuroendocrine tumors of the lung via NanoString nCounter expression analysis.
abstract: BACKGROUND
  Neuroendocrine tumors of the lung comprise typical (TC) and atypical carcinoids (AC), large-cell neuroendocrine cancer (LCNEC) and small-cell lung cancer (SCLC). Cell cycle and apoptosis are key pathways of multicellular homeostasis and deregulation of these pathways is associated with cancerogenesis.
  
  
  METHODS
  Sixty representative FFPE-specimens (16 TC, 13 AC, 16 LCNEC and 15 SCLC) were used for mRNA expression analysis using the NanoString technique. Eight genes related to apoptosis and ten genes regulating key points of cell cycle were investigated.
  
  
  RESULTS
  ASCL1, BCL2, CASP8, CCNE1, CDK1, CDK2, CDKN1A and CDKN2A showed lower expression in carcinoids compared to carcinomas. In contrast, CCNE1 and CDK6 showed elevated expression in carcinoids compared to carcinomas. The calculated BCL2/BAX ratio showed increasing values from TC to SCLC. Between SCLC and LCNEC CDK2, CDKN1B, CDKN2A and PNN expression was significantly different with higher expression in SCLC.
  
  
  CONCLUSIONS
  Carcinoids have increased CDK4/6 and CCND1 expression controlling RB1 phosphorylation via this signaling cascade. CDK2 and CCNE1 were increased in carcinomas showing that these use the opposite way to control RB1. BAX and BCL2 are antagonists in regulating apoptosis. BCL2 expression increased over BAX expression with increasing malignancy of the tumor from TC to SCLC.
authors.affiliation: Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.|Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Robert Fred Henry
authors.initials: RF
authors.lastname: Walter
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Werner
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Ting
authors.affiliation: Institute of Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Vollbrecht
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Theegarten
authors.affiliation: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Daniel Christian
authors.initials: DC
authors.lastname: Christoph
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Kurt Werner
authors.initials: KW
authors.lastname: Schmid
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Jeremias
authors.initials: J
authors.lastname: Wohlschlaeger
authors.affiliation: Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Fabian Dominik
authors.initials: FD
authors.lastname: Mairinger
mesh_terms: D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002276:Carcinoid Tumor / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018287:Carcinoma, Large Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D036103:Nanotechnology / Q000379:methods*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D012333:RNA, Messenger
keywords: NanoString nCounter; Pathology Section; apoptosis; carcinoids; large-cell neuroendocrine lung cancer; small-cell lung cancer