Implication of VHL, ERK5, and HIF-1alpha in clear cell renal cell carcinoma: Molecular basis.
To determine the expression status of several proteins related to VHL gene function and its relationship with common clinicopathological parameters.



Observational, analytical, cross-sectional study with 50 patients diagnosed with clear cell renal cell carcinoma. The study analyzed VHL mutations and hypermethylation as well as protein expression of VHL, CA-IX, HIF-1alpha, VEGF, ERK1/2, and ERK5, relating them to clinical variables. A bivariate and multivariate descriptive logistical regression analysis was performed, using the presence of metastasis at diagnosis as dependent variable.



The study identified 13 (26%) VHL mutations related to nuclear grade (P = 0.036). VHL hypermethylation was found in 20% of cases. VHL expression was associated with the presence of mutations (P = 0.013), and the absence of expression was associated with nuclear grade and the presence of metastasis (P<0.05). HIF-1alpha was negative in only 5 cases. Vascular endothelial growth factor (VEGF) was positive in 31 of 47 cases and was associated with Fuhrman nuclear grade, presence of metastasis, and stage (P<0.05). ERK5 expression was increased in 58% of cases and associated with the presence of metastasis and more advanced stages (P<0.05). In the logistic regression analysis, the only variable remaining in the model was VEGF expression (P = 0.014).



VEGF has prognostic value in clear cell renal cell carcinoma, and ERK5 may be a new prognostic marker in this type of tumor owing to its relationship with metastasis and more advanced stages.
Unidad de Medicina Molecular, Laboratorio de Oncología, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina CSIC-Universidad de Castilla-La Mancha, Albacete, Spain.
Leticia
L
Serrano-Oviedo
Servicio de Urología, Complejo Hospitalario Universitario de Albacete, Albacete, Spain. Electronic address: gbjosem@sescam.jccm.es.
José M
JM
Giménez-Bachs
Servicio de Anatomía Patológica, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
Syongh Y
SY
Nam-Cha
Unidad de Medicina Molecular, Laboratorio de Oncología, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina CSIC-Universidad de Castilla-La Mancha, Albacete, Spain.
Francisco J
FJ
Cimas
Unidad de Medicina Molecular, Laboratorio de Oncología, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina CSIC-Universidad de Castilla-La Mancha, Albacete, Spain.
Jesús
J
García-Cano
Unidad de Medicina Molecular, Laboratorio de Oncología, Centro Regional de Investigaciones Biomédicas, Unidad de Biomedicina CSIC-Universidad de Castilla-La Mancha, Albacete, Spain.
Ricardo
R
Sánchez-Prieto
Servicio de Urología, Complejo Hospitalario Universitario de Albacete, Albacete, Spain.
Antonio S
AS
Salinas-Sánchez
D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor / Q000378:metabolism; D000071231:Carbonic Anhydrase IX / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism
D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D000071231:Carbonic Anhydrase IX; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C535150:MAPK1 protein, human; C481581:MAPK7 protein, human; C089226:CA9 protein, human; C497446:VHL protein, human
Biomarkers; Clear cell renal cell carcinoma; Signaling pathway; VHL