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. 2011;6(8):e23847.
doi: 10.1371/journal.pone.0023847. Epub 2011 Aug 22.

Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival

Sigve Andersen  1 , Tom Donnem, Helge Stenvold, Samer Al-Saad, Khalid Al-Shibli, Lill-Tove Busund, Roy M Bremnes
Affiliations

Overexpression of the HIF hydroxylases PHD1, PHD2, PHD3 and FIH are individually and collectively unfavorable prognosticators for NSCLC survival

Sigve Andersen et al. PLoS One. 2011.

Abstract

Introduction: Hypoxia 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.

Methods: Tumor 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 findings: There 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).

Conclusions: HIF 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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Disease-specific survival according to HIF hydroxylase expression.
Disease-specific Kaplan-Meier survival curves according to: A) PHD1, B) PHD2, C) PHD3 and D) FIH in resected NSCLC patients. The P-value is according to the log-rank test.
Figure 2
Figure 2. Disease-specific survival according to the co-expression of HIF hydroxylases.
Disease-specific Kaplan-Meier survival curves according to the sum of HIF hydroxylases with a high expression in resected NSCLC patients. The P-value is according to the log-rank test.
Figure 3
Figure 3. Immunohistochemical staining.
Immunohistochemical analyses of NSCLC representing high and low intensities for tumor cell expression of PHD1, PHD2, PHD3 and FIH.
See this image and copyright information in PMC

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