TY - JOUR
T1 - Expression of nuclear FIH independently predicts overall survival of clear cell renal cell carcinoma patients
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
PY - 2010/12
Y1 - 2010/12
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.
KW - Factor-inhibiting HIF
KW - Hypoxia
KW - Prognostic marker
KW - Renal cell carcinoma
KW - Tissue microarray
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U2 - 10.1016/j.ejca.2010.07.018
DO - 10.1016/j.ejca.2010.07.018
M3 - Article
C2 - 20709525
AN - SCOPUS:78649630859
SN - 0959-8049
VL - 46
SP - 3375
EP - 3382
JO - European Journal of Cancer
JF - European Journal of Cancer
IS - 18
ER -