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Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma.

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.

SUBMITTER: Papale M

PROVIDER: S-EPMC5522321 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma.

Papale Massimo M Vocino Grazia G Lucarelli Giuseppe G Rutigliano Monica M Gigante Margherita M Rocchetti Maria Teresa MT Pesce Francesco F Sanguedolce Francesca F Bufo Pantaleo P Battaglia Michele M Stallone Giovanni G Grandaliano Giuseppe G Carrieri Giuseppe G Gesualdo Loreto L Ranieri Elena E

Oncotarget 20170601 25

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 pat ...[more]

PMID: 28418894

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Project description:Purpose: In this study, we have undertaken the whole proteomic analysis and got a better understanding of biological processes involved in the development and progression of ccRCC. We hope promising biomarkers can be uncovered to facilitate early diagnosis, predict the prognosis and progression, more importantly, to be applied as potential therapeutic targets. Experimental design: Fresh frozen tissue samples were surgically resected from patients with local or locally advanced ccRCC. Trypsin digested proteins were analyzed using TMT-based LC-MS/MS proteomic approach, followed by bioinformatic analysis. A potential prognostic marker FMNL1, annotated with actin cytoskeleton assembly and cell migration, was chosen to be validated in TCGA_KIRC datasets(n=597), further validation sets(n=20) and expanded validation sets(n=97). Results: A total of 657 differentially expressed proteins were identified and quantified between ccRCC and adjacent normal tissues (p-value<0.05, FC>2 or<1/2), of which 186 proteins were up-regulated and 471 proteins were down-regulated. Bioinformatic analysis showed enriched metabolic biological processes and pathways including oxidative phosphorylation, valine, leucine and isoleucine degeneration, propanoate metabolism, fatty-acid degeneration, TCA cycle, glycolysis/gluconeogenesis, etc. Univariate and multivariate analysis defined FMNL1 as an independent negative prognostic marker in the TCGA datasets. High expression of FMNL1 correlated significantly with tumor stage, T stage, lymph node metastasis(P<0.05), and distant metastasis(P<0.05) both in the TCGA-KIRC datasets and expanded validation sets. And KM survival curve illustrated that patients with high FMNL1 protein level had shorter OS time in the expanded validation sets (p=0.0273) Conclusion and clinical relevance: The proteomic results uncovered sophisticated metabolic reprogramming of ccRCC and indicated that the upregulation of rate-limiting enzymes in glycolysis and mitochondrial impairment may be the cause of metabolic reprogramming in ccRCC. Moreover, FMNL1 has been identified as a diagnostic and prognostic marker, and may be implicated in the progression of ccRCC.

Dataset Information

Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma.

Publications

Urinary RKIP/p-RKIP is a potential diagnostic and prognostic marker of clear cell renal cell carcinoma.

Similar Datasets

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