title: Tumor biology of non-metastatic stages of clear cell renal cell carcinoma; overexpression of stearoyl desaturase-1, EPO/EPO-R system and hypoxia-related proteins.
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinomas. There is great interest to know the molecular basis of the tumor biology of ccRCC that might contribute to a better understanding of the aggressive biological behavior of this cancer and to identify early biomarkers of disease. This study describes the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (hypoxia-inducible factor (HIF)-1α, erythropoietin (EPO), vascular endothelial growth factor (VEGF)), their receptors (EPO-R, VEGFR-2), and stearoyl desaturase-1 (SCD-1) in early stages of ccRCC. Tissue samples were obtained at the Urology Unit of the J.R. Vidal Hospital (Corrientes, Argentina), from patients who underwent radical nephrectomy for renal cancer between 2011 and 2014. Four experimental groups according to pathological stage and nuclear grade were organized: T1G1 (n = 6), T2G1 (n = 4), T1G2 (n = 7), and T2G2 (n = 7). The expression of HIF-1α, EPO, EPO-R, VEGF, VEGFR-2, Bcl-xL, and SCD-1 were evaluated by immunohistochemistry, Western blotting, and/or RT-PCR. Apoptosis was assessed by the TUNEL in situ assay, and tumor proliferation was determined by Ki-67 immunohistochemistry. Data revealed that HIF-1α, EPO, EPO-R, VEGF, and VEGF-R2 were overexpressed in most samples. The T1G1 group showed the highest EPO levels, approximately 200 % compared with distal renal tissue. Bcl-xLoverexpression was concomitant with the enhancement of proliferative indexes. SCD-1 expression increased with the tumor size and nuclear grade. Moreover, the direct correlations observed between SCD-1/HIF-1α and SCD-1/Ki-67 increments suggest a link among these molecules, which would determine tumor progression in early stages of ccRCC. Our results demonstrate the relationship among proliferation, survival, and apoptosis with the expression of key molecules related to tumoral hypoxia (HIF-1α, EPO, VEGF), their receptors (EPO-R, VEGFR-2), and SCD-1 in early stages of ccRCC.
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina.
authors.forename: Tania Romina
authors.initials: TR
authors.lastname: Stoyanoff
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Rodríguez
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina.
authors.forename: Juan Santiago
authors.initials: JS
authors.lastname: Todaro
authors.affiliation: Department of Urology, J.R. Vidal Hospital, Corrientes, Argentina.
authors.forename: Joaquín Diego
authors.initials: JD
authors.lastname: Espada
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina.
authors.forename: Juan Pablo Melana
authors.initials: JP
authors.lastname: Colavita
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina.
authors.forename: Nora Cristina
authors.initials: NC
authors.lastname: Brandan
authors.affiliation: Pharmacology, Faculty of Biochemical and Pharmaceutical Sciences, National University of Rosario (UNR), CONICET, Rosario, Argentina.
authors.forename: Adriana Mónica
authors.initials: AM
authors.lastname: Torres
authors.affiliation: Laboratory of Biochemical Investigations (LIBIM), Basic Medical Sciences Department, School of Medicine, National Northeastern University (UNNE), IQUIBA-CONICET, Moreno 1240, 3400, Corrientes, Argentina. mvaguirre@med.unne.edu.ar.
authors.forename: María Victoria
authors.initials: MV
authors.lastname: Aguirre
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D049109:Cell Proliferation; D004921:Erythropoietin / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D017467:Receptors, Erythropoietin / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C554270:EPO protein, human; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D013230:Stearoyl-CoA Desaturase; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Apoptosis; Clear cell renal cell carcinoma (ccRCC); EPO receptor (EPO-R); Erythropoietin (EPO); Stearoyl desaturase-1 (SCD-1)