Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients

Stephanie G C Kroeze, Joost S. Vermaat, Aram Van Brussel, Harm H E Van Melick, Emile E. Voest, Trudy G N Jonges, Paul J. Van Diest, John Hinrichs, J. L H Ruud Bosch, Judith J M Jans

Research output: Contribution to journalArticle

Abstract

Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results: HIF-1α was positively correlated with HIF-2α (p <0.0001), PHD1 (p = 0.024), PHD2 (p <0.0001), PHD3 (p = 0.004), FIH (p <0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p <0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009). Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

Original languageEnglish (US)
Pages (from-to)3375-3382
Number of pages8
JournalEuropean Journal of Cancer
Volume46
Issue number18
DOIs
StatePublished - Dec 2010
Externally publishedYes

Fingerprint

Renal Cell Carcinoma
Survival
Hypoxia-Inducible Factor 1
Prolyl Hydroxylases
Nephrectomy
Neoplasms
Cell Survival
Cell Proliferation
Neoplasm Metastasis
Gene Expression
Mutation
Hypoxia
endothelial PAS domain-containing protein 1
Proteins

Keywords

  • Factor-inhibiting HIF
  • Hypoxia
  • Prognostic marker
  • Renal cell carcinoma
  • Tissue microarray

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kroeze, S. G. C., Vermaat, J. S., Van Brussel, A., Van Melick, H. H. E., Voest, E. E., Jonges, T. G. N., ... Jans, J. J. M. (2010). Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients. European Journal of Cancer, 46(18), 3375-3382. https://doi.org/10.1016/j.ejca.2010.07.018

Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients. / Kroeze, Stephanie G C; Vermaat, Joost S.; Van Brussel, Aram; Van Melick, Harm H E; Voest, Emile E.; Jonges, Trudy G N; Van Diest, Paul J.; Hinrichs, John; Bosch, J. L H Ruud; Jans, Judith J M.

In: European Journal of Cancer, Vol. 46, No. 18, 12.2010, p. 3375-3382.

Research output: Contribution to journalArticle

Kroeze, SGC, Vermaat, JS, Van Brussel, A, Van Melick, HHE, Voest, EE, Jonges, TGN, Van Diest, PJ, Hinrichs, J, Bosch, JLHR & Jans, JJM 2010, 'Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients', European Journal of Cancer, vol. 46, no. 18, pp. 3375-3382. https://doi.org/10.1016/j.ejca.2010.07.018
Kroeze, Stephanie G C ; Vermaat, Joost S. ; Van Brussel, Aram ; Van Melick, Harm H E ; Voest, Emile E. ; Jonges, Trudy G N ; Van Diest, Paul J. ; Hinrichs, John ; Bosch, J. L H Ruud ; Jans, Judith J M. / Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients. In: European Journal of Cancer. 2010 ; Vol. 46, No. 18. pp. 3375-3382.
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abstract = "Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results: HIF-1α was positively correlated with HIF-2α (p <0.0001), PHD1 (p = 0.024), PHD2 (p <0.0001), PHD3 (p = 0.004), FIH (p <0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p <0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009). Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.",
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AU - Kroeze, Stephanie G C

AU - Vermaat, Joost S.

AU - Van Brussel, Aram

AU - Van Melick, Harm H E

AU - Voest, Emile E.

AU - Jonges, Trudy G N

AU - Van Diest, Paul J.

AU - Hinrichs, John

AU - Bosch, J. L H Ruud

AU - Jans, Judith J M

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N2 - Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results: HIF-1α was positively correlated with HIF-2α (p <0.0001), PHD1 (p = 0.024), PHD2 (p <0.0001), PHD3 (p = 0.004), FIH (p <0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p <0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009). Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

AB - Aim: The hypoxia inducible factor (HIF) pathway plays an important role in sporadic clear cell renal cell carcinoma (ccRCC) by stimulating processes of angiogenesis, cell proliferation, cell survival and metastases formation. Herein, we evaluate the significance of upstream proteins directly regulating the HIF pathway; the prolyl hydroxylases domain proteins (PHD)1, 2 and 3 and factor-inhibiting HIF (FIH), as prognostic markers for ccRCC. Methods: Immunohistochemical marker expression was examined on a tissue microarray containing tumour tissue derived from 100 patients who underwent nephrectomy for ccRCC. Expression levels of HIF, FIH and PHD1, 2 and 3 were correlated with overall survival (OS) and clinicopathological prognostic factors. Results: HIF-1α was positively correlated with HIF-2α (p <0.0001), PHD1 (p = 0.024), PHD2 (p <0.0001), PHD3 (p = 0.004), FIH (p <0.0001) and VHL (p = 0.031). HIF-2α levels were significantly associated with FIH (p <0.0001) and PHD2 (p = 0.0155). Mutations in the VHL gene, expression variations of HIF-1α, HIF-2α and PHD1, 2, 3 did not show a correlation to OS or clinicopathological prognostic factors. Tumour stage, grade, diameter, metastastic disease and intensity of nuclear FIH were significantly correlated to OS in univariable analysis (p = 0.023). Low nuclear FIH levels remained a strong independent prognostic factor in multivariable analysis (p = 0.009). Conclusion: These results show that low nuclear expression of FIH is a strong independent prognostic factor for a poor overall survival in ccRCC.

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