title: Functional and clinical characterization of the putative tumor suppressor WWOX in non-small cell lung cancer.
abstract: BACKGROUND
  The oxidoreductase WWOX was initially described as a putative tumor suppressor in breast cancer. Non-small cell lung cancers (NSCLCs) frequently show aberrant WWOX expression. Herein, we characterized WWOX at a functional level in preclinical NSCLC models and in primary NSCLC biopsies.
  
  
  METHODS
  The human wild-type (wt) WWOX complementary DNA and a mutant WWOX with structurally disrupted short-chain dehydrogenase/reductase domain were conditionally expressed at physiological levels in several human NSCLC models. Resulting transgenic cell populations were analyzed with respect to clonogenic survival and apoptosis sensitivity in vitro and tumor growth in immune-deficient mice. Tissue microarrays prepared from surgically resected primary human NSCLC tumors were studied to correlate intratumoral WWOX expression with patient outcomes.
  
  
  RESULTS
  Conditional expression of wt WWOX, but not mutant WWOX, suppressed clonogenic survival of NSCLC cells in vitro and tumor growth in vivo. In addition, preserved intratumoral WWOX expression was associated with improved outcome in a cohort of 85 patients with surgically resected NSCLC. Unexpectedly, wt WWOX failed to sensitize NSCLC cells to various apoptotic stimuli but robustly protected against apoptosis induced by inhibitors of growth factor signal transduction.
  
  
  CONCLUSIONS
  WWOX acts as a tumor suppressor in human NSCLC models in a short-chain dehydrogenase/reductase domain-dependent manner. This activity is independent of sensitization to apoptotic cell death. WWOX expression as detected by immunohistochemistry may be a prognostic biomarker in surgically resected, early-stage NSCLC.
authors: Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors: Silvan
authors: S
authors: Becker
authors: Boyka
authors: B
authors: Markova
authors: Rainer
authors: R
authors: Wiewrodt
authors: Sandra
authors: S
authors: Hoffarth
authors: Patricia S
authors: PS
authors: Hähnel
authors: Sina
authors: S
authors: Pleiner
authors: Lars Hennig
authors: LH
authors: Schmidt
authors: Frank
authors: F
authors: Breitenbuecher
authors: Martin
authors: M
authors: Schuler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology* / Q000601:surgery; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology* / Q000601:surgery; D051379:Mice; D010088:Oxidoreductases / Q000378:metabolism*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000074584:WW Domain-Containing Oxidoreductase
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; D000074584:WW Domain-Containing Oxidoreductase; C486071:WWOX protein, human