MiR501-5p may promote proliferation and survival in clear cell kidney carcinoma

Abstract

MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression and are involved in the control of several biological processes such as proliferation differentiation and apoptosis. The abnormal expression and mutation of miRs is implicated in many hereditary and neoplastic diseases including kidney carcinoma. In the last years, is emerging the necessity to use microRNA as biological biomarkers in order to improve diagnosis, prognosis and therapy response in renal carcinomas. Furthermore, miRNAs might be potential targets for novel therapeutic strategies, especially in patients that are resistant to conventional treatments. We have found that the expression of miR501-5p was higher in 35 clear cell carcinoma (ccRCC) and lower in 9 papillary carcinoma (pRCC) tissues compared with their corresponding normal kidney parenchyma. The expression levels of miR501-5p were not associated with the age of patients or tumor grading in ccRCC and, showed a variable distribution. However, patients with a low expression of miR501-5p exhibited a good prognosis compared with patient with unchanged or high levels of this miR. In order to evaluate the possible role of miR501-5p in renal cancer, we have downregulated and upregulated it by transfection of kidney carcinoma cells (KJ29) with a specific antagomiR and with a plasmid expressing miR501-5p sequences, respectively. The reduction of miR501-5p induced an increase in G0/G1 phase and a decrease of mTOR activity. In addition, the treatment with antagomiR showed an increase in both p53 expression and caspase-3 activity. Consistently, the activation of p53 was demonstrated also by its nuclear translocation. On the contrary, the overexpression of miR501-5p by transfection of KJ29 cells with the plasmid expressing this miR caused the activation of mTOR, the increased expression of MDM2 protein, an inhibitor of p53, and, the reduction of p53 expression. The inhibition of p53 occurred by its degradation through protein ubiquitination and activation of proteasoma machinery which induced a marked increase of cell survival. Taken together, these findings show that the overexpression of miR501-5p may increase cell survival, therefore an high expression of this MicroRNA could be a risk factor for a poor prognosis of renal carcinoma. Conversely, a low expression of miR501-5p seems promote a good prognosis in clear cell kidney carcinoma patients. Thus, the expression of miR501-5p could be used as new potential biomarker for the prognosis of clear cell renal carcinoma