title: Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma.
abstract: Renal cell carcinoma is a common neoplasia of the adult kidney that accounts for about 3% of adult malignancies. Clear cell renal carcinoma is the most frequent subtype of kidney cancer and 20-40% of patients develop metastases. The absence of appropriate biomarkers complicates diagnosis and prognosis of this disease. In this regard, small noncoding RNAs (microRNAs), which are mutated in several neoplastic diseases including kidney carcinoma, may be optimal candidates as biomarkers for diagnosis and prognosis of this kind of cancer. Here we show that patients with clear cell kidney carcinoma that express low levels of miR501-5p exhibited a good prognosis compared with patients with unchanged or high levels of this microRNA. Consistently, in kidney carcinoma cells the downregulation of miR501-5p induced an increased caspase-3 activity, p53 expression as well as decreased mTOR activation, leading to stimulation of the apoptotic pathway. Conversely, miR501-5p upregulation enhanced the activity of mTOR and promoted both cell proliferation and survival. These biological processes occurred through p53 inactivation by proteasome degradation in a mechanism involving MDM2-mediated p53 ubiquitination. Our results support a role for miR501-5p in balancing apoptosis and cell survival in clear cell renal carcinoma. In particular, the downregulation of microRNA501-5p promotes a good prognosis, while its upregulation contributes to a poor prognosis, in particular, if associated with p53 and MDM2 overexpression and mTOR activation. Thus, the expression of miR501-5p is a possible biomarker for the prognosis of clear cell renal carcinoma.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Via Fossato di Mortara 64/b, 44121 Ferrara, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mangolini
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Bonon
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Anatomy and Histology, University of Ferrara, Via Fossato di Mortara 64/b, 44121 Ferrara, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Volinia
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathological Anatomy and Biomolecular Diagnostic, Azienda Ospedaliero Universitaria, Via Aldo Moro 8, 44124 Ferrara, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Lanza
authors.affiliation: Department of Life Sciences and Biotechnologies, Section of Molecular Biology, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, Section of Pathology, Oncology and Experimental Biology, University of Ferrara, Via Fossato di Mortara 64/b, 44121 Ferrara, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pinton
authors.affiliation: Unit of Urology, St. Anna Hospital, Via Aldo Moro 8, 44124 Ferrara, Italy.
authors.forename: Gian Rosario
authors.initials: GR
authors.lastname: Russo
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Del Senno
authors.affiliation: Unit of Urology, St. Anna Hospital, Via Aldo Moro 8, 44124 Ferrara, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Dell'Atti
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Section of Biochemistry, Molecular Biology and Medical Genetics, University of Ferrara, Via Fossato di Mortara 74, 44121 Ferrara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Aguiari
keywords: Apoptosis; Cell survival; MDM2, mouse double minute 2 homolog; MicroRNA501-5p; ccRCC, clear cell renal cell carcinoma; mTOR signaling; mTOR, mammalian target of rapamycin; p53; pRCC, papillary renal cell carcinoma