Differential expression of microRNA501-5p affects the aggressiveness of clear cell renal carcinoma

• Published in: FEBS open bio 2014-01, Vol.4 (1), p.952-965
• Main Authors: Mangolini, Alessandra, Bonon, Anna, Volinia, Stefano, Lanza, Giovanni, Gambari, Roberto, Pinton, Paolo, Russo, Gian Rosario, del Senno, Laura, Dell’Atti, Lucio, Aguiari, Gianluca
• Format: Article
• Language: English
• Subjects: Apoptosis; Biomarkers; Cancer therapies; Caspase; Cell growth; Cell proliferation; Cell survival; Clear cell-type renal cell carcinoma; Diagnosis; Gene expression; Kidney cancer; Kidneys; Kinases; Laboratories; MDM2 protein; Medical prognosis; Metastases; Metastasis; MicroRNA501-5p; MicroRNAs; miRNA; Morphology; mTOR signaling; Mutation; p53; p53 Protein; Prognosis; Proteasomes; Proteins; TOR protein; Tumors; Ubiquitination
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1016/j.fob.2014.10.016

•Low expression of miR501-5p correlates with good prognosis for patients with ccRCC.•miRNA501-5p downregulation stimulates apoptosis by p53 activation.•miR501-5p upregulation promotes cell proliferation and survival.•Increased cell growth occurs by activation of mTOR kinase and MDM2 expression.•This miRNA modulates apoptosis/cell growth, making it a prognostic biomarker for ccRCC. 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.