title: Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance.
abstract: OBJECTIVE
  High inhibitor of differentiation-1 (Id1) levels have been found in some tumor types. We aimed to study Id1 levels and their prognostic impact in a large series of stages I to IV non-small cell lung cancer (NSCLC) patients. Experiments in cell lines and cells derived from malignant pleural effusions (MPE) were also carried out.
  
  
  METHODS
  A total of 346 NSCLC samples (three different cohorts), including 65 matched nonmalignant tissues, were evaluated for Id1 expression by using immunohistochemistry. Additional data from a fourth cohort including 111 patients were obtained for Id1 mRNA expression analysis by using publicly available microarrays. In vitro proliferation assays were conducted to characterize the impact of Id1 on growth and treatment sensitivity.
  
  
  RESULTS
  Significantly higher Id1 protein levels were found in tumors compared with normal tissues (P < 0.001) and in squamous carcinomas compared with adenocarcinomas (P < 0.001). In radically treated stages I to III patients and stage IV patients treated with chemotherapy, higher Id1 levels were associated with a shorter disease-free survival and overall survival in adenocarcinoma patients in a log-rank test. A Cox model confirmed the independent prognostic value of Id1 levels for both stages I to III and stage IV patients. In silico analysis confirmed a correlation between higher Id1 mRNA levels and poor prognosis for adenocarcinoma subjects. In vitro Id1 silencing in radio/chemotherapy-resistant adenocarcinoma cells from MPEs restored sensitivity to both therapies.
  
  
  CONCLUSIONS
  In our series, Id1 levels showed an independent prognostic value in patients with adenocarcinoma, regardless of the stage. Id1 silencing may sensitize adenocarcinoma cells to radiotherapy and chemotherapy.
authors.affiliation: Departments of Oncology, Pathology, and Thoracic Surgery, Clínica Universidad de Navarra; Division of Oncology, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Ponz-Sarvisé
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nguewa
authors.forename: María J
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: María D
authors.initials: MD
authors.lastname: Lozano
authors.forename: Miriam
authors.initials: M
authors.lastname: Redrado
authors.forename: Ruben
authors.initials: R
authors.lastname: Pio
authors.forename: Carmen
authors.initials: C
authors.lastname: Behrens
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Carlos E
authors.initials: CE
authors.lastname: García-Franco
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Foncillas
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Alfonso
authors.initials: A
authors.lastname: Calvo
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gil-Bazo
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis* / Q000401:mortality / Q000503:physiopathology* / Q000628:therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism*; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering