Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma
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Massimo Papale1,3, Grazia Vocino1, Giuseppe Lucarelli2, Monica Rutigliano2, Margherita Gigante3, Maria Teresa Rocchetti3, Francesco Pesce3, Francesca Sanguedolce4, Pantaleo Bufo4, Michele Battaglia2, Giovanni Stallone5, Giuseppe Grandaliano5, Giuseppe Carrieri6, Loreto Gesualdo3 and Elena Ranieri1
1Molecular Medicine Center, Section of Clinical Pathology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
2Division of Urology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
3Division of Nephrology, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy
4Department of Pathology, University of Foggia, Foggia, Italy
5Division of Nephrology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
6Division of Urology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
Elena Ranieri, email: [email protected]
Keywords: RKIP, phospho-RKIP, biomarkers, urine, clear cell renal cell carcinoma
Received: September 13, 2016 Accepted: February 21, 2017 Published: March 18, 2017
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-off value 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.
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