title: Glycine decarboxylase and HIF-1α expression are negative prognostic factors in primary resected early-stage non-small cell lung cancer.
abstract: Glycine decarboxylase (GLDC) was recently described as a critical enzyme of tumor-initiating cells and, thus, a driver of tumorigenesis in lung non-small cell cancer (NSCC). It is important in metabolism under hypoxic conditions. Hypoxia-inducible factor 1-alpha (HIF-1α) is the unique subunit that determines HIF system activity, thereby regulating the adverse effects of hypoxia on cancer outcome. We examined the expression and prognostic significance of GLDC and HIF-1α in primary resected stage I/II NSCC. Immunohistochemistry for GLDC and HIF-1α was validated on two lung NSCC cell lines (A549, NCI-H460) and evaluated on a tissue microarray with 428 lung NSCC: 184 adenocarcinomas, 211 squamous cell carcinomas, and 33 large cell carcinomas (LCC). The results were correlated with clinico-pathological parameters. High levels of GLDC expression were detected in 33/428 cases (7.7%). HIF-1α was expressed in 71 (16.6%) cases and more frequently in squamous cell carcinoma (p < 0.001). Significantly longer survival was seen in younger patients (p = 0.007), patients with non-LCC histology (p = 0.006), lower primary tumor category (p = 0.002), and Union for International Cancer Control (UICC) stage (p = 0.001). Both GLDC and HIF-1α were significantly associated with worse tumor-related survival (p = 0.013, p = 0.021, respectively), although not independent from each other in multivariate models. The combination of low-GLDC/negative HIF-1α expression was significantly prognostic for longer survival (p = 0.002) and emerged as an independent prognostic factor in multivariate analysis (p = 0.007, HR 2.052), next to UICC stage and age. We show that the combination of GLDC and HIF-1α expression is an independent prognostic factor in early-stage NSCC. Our results will assist future development of therapeutic approaches targeting GLDC or exploiting tumor hypoxia.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Sabina
authors.initials: S
authors.lastname: Berezowska
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: José A
authors.initials: JA
authors.lastname: Galván
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.|Promed SA Laboratoire Medical, Fribourg, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gugger
authors.affiliation: Division of General Thoracic Surgery, Inselspital, Bern University Hospital, Department of Clinical Research, University of Bern, Murtenstrasse 50, 3008, Bern, Switzerland.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Schmid
authors.affiliation: Division of General Thoracic Surgery, Inselspital, Bern University Hospital, Department of Clinical Research, University of Bern, Murtenstrasse 50, 3008, Bern, Switzerland. thomas.marti@insel.ch.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Marti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000032:analysis / Q000096:biosynthesis*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis / Q000096:biosynthesis*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050841:Glycine Dehydrogenase (Decarboxylating)
keywords: Glycine decarboxylase; HIF-1α; Hypoxia; Immunohistochemistry; NSCC