Abstract
IntroductionHypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. HIFs are regulated by four hydroxylases; Prolyl hydroxylase (PHD)-1,-2,-3 and factor inhibiting HIF (FIH). We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC.MethodsTumor tissue samples from 335 resected stages I to IIIA NSCLC patients was obtained and tissue microarrays (TMAs) were constructed. Hydroxylase expression was evaluated by immunohistochemistry.Principal FindingsThere was scorable expression for all HIF hydroxylases in tumor cells, but not in stroma. In univariate analyses, high tumor cell expression of all the HIF hydroxylases were unfavorable prognosticators for disease-specific survival (DSS); PHD1 (P = 0.023), PHD2 (P = 0.013), PHD3 (P = 0.018) and FIH (P = 0.033). In the multivariate analyses we found high tumor cell expression of PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for DSS. Besides, there was an additive prognostic effect by the increasing number of highly expressed HIF hydroxylases. Provided none high expression HIF hydroxylases, the 5-year survival was 80% vs. 23% if all four were highly expressed (HR = 6.48, CI 95% 2.23–18.8, P = 0.001).ConclusionsHIF hydroxylases are, in general, poor prognosticators for NSCLC survival. PHD1 and PHD2 are independent negative prognostic factors in NSCLC. Moreover, there is an additive poor prognostic impact by an increasing number of highly expressed HIF hydroxylases.
Highlights
Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival
Hypoxia is a feature of many NSCLC tumors [3] and the ability of tumor cells to adapt to a reduced oxygen and nutrient supply is vital for their survival [4]
Model 1 we found high tumor cell expression of the PHD2 (HR = 2.03, CI 95% 1.20–3.42, P = 0.008) and PHD1 (HR = 1.45, CI 95% 1.01–2.10, P = 0.047) to be significant independent prognosticators for disease-specific survival (DSS) in addition to several clinicopathological variables
Summary
Hypoxia induced factors (HIFs) are at the heart of the adaptive mechanisms cancer cells must implement for survival. We aimed to investigate the prognostic impact of these oxygen sensors in NSCLC. Eighty to 85% of lung cancers are of non-small cell type (NSCLC). NSCLC is potentially curable by surgery [2], but even among tumor-resected patients lung cancer mortality remains high. Hypoxia is a feature of many NSCLC tumors [3] and the ability of tumor cells to adapt to a reduced oxygen and nutrient supply is vital for their survival [4]. When oxygen tension is reduced, the HIF transcription factors, composed of the subunits HIFa (HIF1a, HIF2a or HIF3a) and HIFb, are at the heart of these mechanisms
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