title: Erk/MAP kinase signaling pathway and neuroendocrine differentiation of non-small-cell lung cancer.
abstract: BACKGROUND
  Almost all small-cell lung cancers (SCLC) and carcinoid tumors express neuroendocrine differentiation (NED), and 10% to 20% of non-small-cell lung cancers (NSCLC) are associated with NED. Although distinct clinical features and histology of SCLC and carcinoid tumors are well recognized, the clinical significance and the molecular basis of NED in NSCLC remain unclear.
  
  
  METHODS
  To explore the potential molecular pathway involved in NED of NSCLC and its clinical relevance, we conducted investigations using an NSCLC cell line (NCI-H157) as a NED induction model, and explored the potential intracellular signal transduction pathways involved in NED of NSCLC. We confirmed our findings using activators versus inhibitors to these signal transduction pathways in vitro. We also performed immunohistochemical stains of phospho-Erk1/2 of lung cancer specimens known to have NED and explored its clinical relevance.
  
  
  RESULTS
  We discovered that NED of NSCLC was associated with the activation of Erk1/2-mitogen-activated protein kinases (MAPK) signal transduction pathway, and the inhibition of the Akt signal transduction pathway. Using specific activator (Pb) and inhibitors (siRNA-Erk1/2 and U0126) to the Erk1/2-MAP-kinase pathway, as well as the inhibitor (LY294002) to the Akt pathway, we found that Erk1/2-MAP-kinase activation was essential for NED of NCI-H157 cells. Staining of Erk1/2-MAP-kinase pathway revealed a high rate of positivity in NSCLC tumors with NED when compared with other neuroendocrine lung tumors.
  
  
  CONCLUSIONS
  To our knowledge, our findings are the first to describe the potential involvement of Erk/MAPK signal transduction pathway of NSCLC in the association with NED. Further investigation of the Erk/MAPK signal transduction pathway of NSCLC may yield discoveries in identifying specific molecular targets for the treatment of NSCLC with NED.
authors.affiliation: *Department of Radiation Oncology, University of Rochester Medical Center, James P. Wilmot Cancer Center, Rochester, New York; †Department of Pathology & Laboratory Medicine, Institute of Molecular Medicine, University of California, Los Angeles, California; and ‡Department of Pathology & Laboratory Medicine, University of Rochester Medical Center. Rochester, New York.
authors.forename: Yuhchyau
authors.initials: Y
authors.lastname: Chen
authors.forename: Irena
authors.initials: I
authors.lastname: Nowak
authors.forename: Jiaoti
authors.initials: J
authors.lastname: Huang
authors.forename: Peter C
authors.initials: PC
authors.lastname: Keng
authors.forename: Hongliang
authors.initials: H
authors.lastname: Sun
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Wei
authors.forename: Soo Ok
authors.initials: SO
authors.lastname: Lee
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D007854:Lead / Q000494:pharmacology; D008175:Lung Neoplasms / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology*; D009490:Neurosecretory Systems / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000032:analysis; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
chemical_list: D002070:Butadienes; D009570:Nitriles; C113580:U 0126; D007854:Lead; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases; D010751:Phosphopyruvate Hydratase