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The relationship of erythropoietin overexpression with von Hippel-Lindau tumour suppressor gene mutations between hypoxia-inducible factor-1α and -2α in sporadic clear cell renal carcinoma.
Int J Mol Med. 2010 Dec; 26(6):907-12.IJ

Abstract

Decreased levels of von Hippel-Lindau (VHL) tumour suppressor protein are associated with up-regulation of hypoxia-inducible factor (HIF), leading to increased tumour proliferation, angiogenesis and progression. The role of erythropoietin (EPO), a target gene for HIF, remains unknown for sporadic clear cell renal cell carcinoma (sCCRCC). In this study, we determined expression levels of EPO, and its correlation with VHL mutations and HIF-1α and HIF-2α expression in 82 patients identified with sCCRCC following nephrectomy. We identified VHL gene alterations using multiplex polymerase chain reaction, purifying products of polymerase chain reaction, and direct sequencing. Immunohistochemical staining for HIF-1α, HIF-2α and EPO was performed for tumour and corresponding normal tissues. Data were analyzed with respect to clinicopathological factors. EPO was detected in 87.8% of sCCRCC tumours versus 7.3% for normal tissues. EPO expression was related to tumours demonstrating VHL gene abnormalities. Of specimens with VHL alterations 95.6% tested positive for EPO, versus 78.3% when VHL gene expression was normal (P<0.01). EPO was identified in 96.2 and 94.2% of HIF-1α and HIF-2α positive specimens, respectively, compared to 72.4 and 53.8% for HIF-1α and HIF-2α negative groups (p<0.01). Moreover, EPO expression correlated significantly with increasing nuclear grade (p<0.05). HIF-2α was identified in 84.1% of sCCRCC, compared to 64.6% for HIF-1α. Expression of HIF-1α, HIF-2α and EPO is common in sCCRCC. Although both forms of HIF up-regulate expression of EPO, the relationship to HIF-2α appears to be more pronounced. The VHL-HIF-EPO pathway requires further study, as it may represent a potential molecular target for therapy of sCCRCC.

Authors+Show Affiliations

Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, No. 8 Xishiku Street, Xicheng, Beijing, P.R. China. gongkan2004@yahoo.com.cnNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

21042786

Citation

Gong, Kan, et al. "The Relationship of Erythropoietin Overexpression With Von Hippel-Lindau Tumour Suppressor Gene Mutations Between Hypoxia-inducible Factor-1α and -2α in Sporadic Clear Cell Renal Carcinoma." International Journal of Molecular Medicine, vol. 26, no. 6, 2010, pp. 907-12.
Gong K, Zhang N, Zhang K, et al. The relationship of erythropoietin overexpression with von Hippel-Lindau tumour suppressor gene mutations between hypoxia-inducible factor-1α and -2α in sporadic clear cell renal carcinoma. Int J Mol Med. 2010;26(6):907-12.
Gong, K., Zhang, N., Zhang, K., & Na, Y. (2010). The relationship of erythropoietin overexpression with von Hippel-Lindau tumour suppressor gene mutations between hypoxia-inducible factor-1α and -2α in sporadic clear cell renal carcinoma. International Journal of Molecular Medicine, 26(6), 907-12.
Gong K, et al. The Relationship of Erythropoietin Overexpression With Von Hippel-Lindau Tumour Suppressor Gene Mutations Between Hypoxia-inducible Factor-1α and -2α in Sporadic Clear Cell Renal Carcinoma. Int J Mol Med. 2010;26(6):907-12. PubMed PMID: 21042786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The relationship of erythropoietin overexpression with von Hippel-Lindau tumour suppressor gene mutations between hypoxia-inducible factor-1α and -2α in sporadic clear cell renal carcinoma. AU - Gong,Kan, AU - Zhang,Ning, AU - Zhang,Kai, AU - Na,Yanqun, PY - 2010/11/3/entrez PY - 2010/11/3/pubmed PY - 2011/3/9/medline SP - 907 EP - 12 JF - International journal of molecular medicine JO - Int J Mol Med VL - 26 IS - 6 N2 - Decreased levels of von Hippel-Lindau (VHL) tumour suppressor protein are associated with up-regulation of hypoxia-inducible factor (HIF), leading to increased tumour proliferation, angiogenesis and progression. The role of erythropoietin (EPO), a target gene for HIF, remains unknown for sporadic clear cell renal cell carcinoma (sCCRCC). In this study, we determined expression levels of EPO, and its correlation with VHL mutations and HIF-1α and HIF-2α expression in 82 patients identified with sCCRCC following nephrectomy. We identified VHL gene alterations using multiplex polymerase chain reaction, purifying products of polymerase chain reaction, and direct sequencing. Immunohistochemical staining for HIF-1α, HIF-2α and EPO was performed for tumour and corresponding normal tissues. Data were analyzed with respect to clinicopathological factors. EPO was detected in 87.8% of sCCRCC tumours versus 7.3% for normal tissues. EPO expression was related to tumours demonstrating VHL gene abnormalities. Of specimens with VHL alterations 95.6% tested positive for EPO, versus 78.3% when VHL gene expression was normal (P<0.01). EPO was identified in 96.2 and 94.2% of HIF-1α and HIF-2α positive specimens, respectively, compared to 72.4 and 53.8% for HIF-1α and HIF-2α negative groups (p<0.01). Moreover, EPO expression correlated significantly with increasing nuclear grade (p<0.05). HIF-2α was identified in 84.1% of sCCRCC, compared to 64.6% for HIF-1α. Expression of HIF-1α, HIF-2α and EPO is common in sCCRCC. Although both forms of HIF up-regulate expression of EPO, the relationship to HIF-2α appears to be more pronounced. The VHL-HIF-EPO pathway requires further study, as it may represent a potential molecular target for therapy of sCCRCC. SN - 1791-244X UR - https://www.unboundmedicine.com/medline/citation/21042786/The_relationship_of_erythropoietin_overexpression_with_von_Hippel_Lindau_tumour_suppressor_gene_mutations_between_hypoxia_inducible_factor_1α_and__2α_in_sporadic_clear_cell_renal_carcinoma_ L2 - http://www.spandidos-publications.com/ijmm/26/6/907 DB - PRIME DP - Unbound Medicine ER -