Glycine decarboxylase and HIF-1α expression are negative prognostic factors in primary resected early-stage non-small cell lung cancer
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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.
KeywordsNSCC Glycine decarboxylase Hypoxia HIF-1α Immunohistochemistry
The authors gratefully acknowledge the Translational Research Unit of the Institute of Pathology for the excellent technical support on this project. The authors would like to acknowledge Dr. Gary Howard for editing the manuscript concerning the appropriate usage of English. This work was supported by the Bernese Cancer League and the Swiss Cancer Research (KFS-3530-08-2014) to TMM. Those providing funding support for the research were not involved in the study design, collection, analysis and interpretation of data, or writing of the report.
Compliance with ethical standards
This study was approved by the local ethics committees of both institutions and has been performed in accordance with the ethical standards laid down in the 1964 Helsinki Declaration and its later amendments.
Conflict of interest
The authors declare that they have no conflict of interest.
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