TY - JOUR
T1 - Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma
AU - Papale, Massimo
AU - Vocino, Grazia
AU - Lucarelli, Giuseppe
AU - Rutigliano, Monica
AU - Gigante, Margherita
AU - Rocchetti, Maria Teresa
AU - Pesce, Francesco
AU - Sanguedolce, Francesca
AU - Bufo, Pantaleo
AU - Battaglia, Michele
AU - Stallone, Giovanni
AU - Grandaliano, Giuseppe
AU - Carrieri, Giuseppe
AU - Gesualdo, Loreto
AU - Ranieri, Elena
PY - 2017
Y1 - 2017
N2 - Clear cell Renal Cell Carcinoma (ccRCC) causes over 13,000 deaths each year, and about 20,000 new cases/year in Europe. In most cases, the causes are unknown and, most importantly, there are no reliable biomarkers for the diagnosis and prognosis of this disease. The search for sensitive biomarkers for early diagnosis and prognosis of clear cell Renal Cell Carcinoma (ccRCC) is currently a fast growing field. We carried out proteomics analysis of 93 urinary samples of healthy subjects (HS) and patients affected by ccRCC, prostate cancer (PCa) and chronic kidney disease (CKD), that was able to successfully distinguish each group. The most significant candidate biomarker was identified by mass spectrometry as Raf Kinase Inhibitor Protein (RKIP), a key regulator of cell signaling, already described in several cancer types as a metastasis suppressor. By combining ELISA, immunoblotting and tissue microarray, we demonstrated that, in ccRCC, urinary excretion of RKIP and its phosphorylated form (p-RKIP) reflected the tissue expression of these putative biomarkers. Baseline urinary RKIP, evaluated in an independent cohort of 56 ccRCC patients and 28 HS, successfully distinguished both groups and, most importantly, a cut-offvalue of 10 ng/mg/g Pr/uCr enabled a highly accurate prediction of Cancer-specific survival and Progression-free survival. Furthermore, p-RKIP was totally undetectable in both tissue and urine samples of ccRCC, showing a great potential for diagnostics purposes. Our data indicate that urinary RKIP encompasses both the unphosphorylated and the phosphorylated form and that their combined evaluation can help in the diagnosis and prognosis of ccRCC.
AB - Clear cell Renal Cell Carcinoma (ccRCC) causes over 13,000 deaths each year, and about 20,000 new cases/year in Europe. In most cases, the causes are unknown and, most importantly, there are no reliable biomarkers for the diagnosis and prognosis of this disease. The search for sensitive biomarkers for early diagnosis and prognosis of clear cell Renal Cell Carcinoma (ccRCC) is currently a fast growing field. We carried out proteomics analysis of 93 urinary samples of healthy subjects (HS) and patients affected by ccRCC, prostate cancer (PCa) and chronic kidney disease (CKD), that was able to successfully distinguish each group. The most significant candidate biomarker was identified by mass spectrometry as Raf Kinase Inhibitor Protein (RKIP), a key regulator of cell signaling, already described in several cancer types as a metastasis suppressor. By combining ELISA, immunoblotting and tissue microarray, we demonstrated that, in ccRCC, urinary excretion of RKIP and its phosphorylated form (p-RKIP) reflected the tissue expression of these putative biomarkers. Baseline urinary RKIP, evaluated in an independent cohort of 56 ccRCC patients and 28 HS, successfully distinguished both groups and, most importantly, a cut-offvalue of 10 ng/mg/g Pr/uCr enabled a highly accurate prediction of Cancer-specific survival and Progression-free survival. Furthermore, p-RKIP was totally undetectable in both tissue and urine samples of ccRCC, showing a great potential for diagnostics purposes. Our data indicate that urinary RKIP encompasses both the unphosphorylated and the phosphorylated form and that their combined evaluation can help in the diagnosis and prognosis of ccRCC.
KW - Adult
KW - Biomarkers
KW - Biomarkers, Tumor
KW - Carcinoma, Renal Cell
KW - Clear cell renal cell carcinoma
KW - Disease-Free Survival
KW - Enzyme-Linked Immunosorbent Assay
KW - Europe
KW - Humans
KW - Kaplan-Meier Estimate
KW - Kidney Neoplasms
KW - Phosphatidylethanolamine Binding Protein
KW - Phospho-RKIP
KW - Phosphorylation
KW - RKIP
KW - Renal Insufficiency, Chronic
KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
KW - Tissue Array Analysis
KW - Urine
KW - Adult
KW - Biomarkers
KW - Biomarkers, Tumor
KW - Carcinoma, Renal Cell
KW - Clear cell renal cell carcinoma
KW - Disease-Free Survival
KW - Enzyme-Linked Immunosorbent Assay
KW - Europe
KW - Humans
KW - Kaplan-Meier Estimate
KW - Kidney Neoplasms
KW - Phosphatidylethanolamine Binding Protein
KW - Phospho-RKIP
KW - Phosphorylation
KW - RKIP
KW - Renal Insufficiency, Chronic
KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
KW - Tissue Array Analysis
KW - Urine
UR - http://hdl.handle.net/10807/155023
U2 - 10.18632/oncotarget.16341
DO - 10.18632/oncotarget.16341
M3 - Article
SN - 1949-2553
VL - 8
SP - 40412
EP - 40424
JO - Oncotarget
JF - Oncotarget
ER -