Abstract
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.
Highlights
Clear cell Renal cell carcinoma has the third highest mortality rate among genitourinary cancers, with an estimated 13,000 deaths/year reflecting a steady trend toward an increased incidence of this cancer by 2–3% per year [1]
We report the utility of urinary detection of Raf Kinase Inhibitor Protein (RKIP) and p-RKIP to improve the diagnosis and determine the prognosis of clear cell Renal Cell Carcinoma (ccRCC)
The gel spots in the mass range between 20 and 25 kDa were purified from the 2-DE map and run on SELDI ProteinChip to pinpoint the one corresponding to the 23,322 m/z peak, that was identified as RKIP by MALDI-TOF/MS-MS
Summary
Clear cell Renal cell carcinoma (ccRCC) has the third highest mortality rate among genitourinary cancers, with an estimated 13,000 deaths/year reflecting a steady trend toward an increased incidence of this cancer by 2–3% per year [1]. The key to making an early diagnosis for ccRCC is the identification of molecular tumor markers for testing in whole risk populations by easy routine assays. Many molecules such as C-reactive protein, CA15-3, αKlotho and some metabolic enzymes have been investigated, but none of these biomarkers have been definitively validated and their use is not recommended in clinical practice [10,11,12,13,14]. We designed a proteomics-based discovery approach that allowed the identification of Raf Kinase Inhibitor Protein (RKIP) and phosphor-RKIP (p-RKIP) as novel urine biomarkers of ccRCC, that can be useful for both differential diagnosis and prognosis of ccRCC
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