The occurrence of drug resistance limits the efficacy of platinum compounds in the cure of ovarian carcinoma. Since microRNAs (miRNAs) may contribute to this phenomenon by regulating different aspects of tumor cell response, the aim of a recent study by researchers from Istituto Nazionale dei Tumori sought to exploit the analysis of expression of miRNAs in platinum sensitive/resistant cells in an attempt to identify potential regulators of drug response.

In their study, miR-483-3p, which may participate in apoptosis and cell proliferation regulation, was found up-regulated in 4 platinum resistant variants, particularly in the IGROV-1/Pt1 subline, versus parental cells. Transfection of a synthetic precursor of miR-483-3p in IGROV-1 parental cells elicited a marked up-regulation of the miRNA levels. Growth-inhibition and colony-forming assays indicated that miR-483-3p over-expression reduced cell growth and conferred mild levels of cisplatin resistance in IGROV-1 cells, by interference with their proliferative potential.

Using LC Sciences target prediction analysis, the targets of miR-483-3p included PRKCA (encoding PKC-alpha), previously reported to be associated to platinum-resistance in ovarian carcinoma. Researchers found that miR-483-3p directly targeted PRKCA in IGROV-1 cells. In keeping with this finding, cisplatin sensitivity of IGROV-1 cells decreased upon molecular/pharmacological inhibition of PKC-alpha.

Overall, these results suggest that overexpression of miR-483-3p by ovarian carcinoma platinum-resistant cells may interfere with their proliferation, thus protecting them from DNA damage induced by platinum compounds and ultimately representing a drug-resistance mechanism. The impairment of cell growth may account for low levels of drug resistance that could be relevant in the clinical setting.

Expression of miR-483-3p and cisplatin sensitivity after transfection with the miR-483-3p inhibitor in IGROV-1/Pt1 cells

LC Sciences

(a) Bar graph showing expression levels of miR-483-3p at different time points (24, 48 and 72 h) after transfection with the miR-483-3p inhibitor. Data are reported as Relative Quantification (RQ). The small RNA SNORD48 was used as endogenous control to normalize qRT-PCR data. Untransfected cells were used as calibrator. P < 0.05 by two-side Student’s t-test of Negative Control versus miR-483-3p transfected cells (48 h). (b) Untrasfected cells (circle), Negative Control- (square) or miR-483-3p inhibitor- (triangle) transfected cells were treated with cisplatin for 1 h, and counted 72 h later. Values are the mean (± SD, standard deviation) of at least three independent experiments.

 

Reference
N. Arrighettia, , G. Cossaa, L. De Ceccob, S. Stucchia, N. Careninia, E. Cornaa, P. Gandellinia, N. Zaffaronia, P. Peregoa, L. Gatti (2016) PKC-alpha modulation by miR-483-3p in platinum-resistant ovarian carcinoma cells Toxicol Appl Pharmacol. 310(1) 9-19doi: 10.1016/j.taap.2016.08.005 [abstract]

New Findings Suggest Hormonal Alterations that Accompany Superovulation Negatively Impact Endometrial Development MiR-214 May Represent a Novel Therapeutic Target for Diabetic Nephropathy