title: Over-expression of miR-31 or loss of KCNMA1 leads to increased cisplatin resistance in ovarian cancer cells.
abstract: Ovarian cancers have a high mortality rate; this is in part due to resistance to the platinum-based compounds used in chemotherapy. In this paper, we assess the role of microRNA-31 in the development of chemoresistance to cisplatin. We used previous data from microarray experiments to identify potential microRNAs (miRNAs) involved in chemoresistance. The functional significance of these microRNAs was tested using miRNA mimics. We used RNA-seq to identify pathways and genes de-regulated in the resistant cell line and then determined their role using RNAi. Analysis of publically available datasets reveals the potential clinical significance. Our data show that miR-31 is increased, whilst potassium channel calcium activated large conductance subfamily M alpha, member 1 (KCNMA1), a subunit of calcium-regulated big potassium (BK) channels, is reduced in resistant ovarian cells. Over-expression of miR-31 increased resistance, as did knockdown of KCNMA1 or inhibition of BK channels. This suggests that these genes directly modulate cisplatin response. Our data also suggest that miR-31 represses KCNMA1 expression. Comparing the levels of miR-31 and KCNMA1 to cisplatin resistance in the NCI60 panel or chemoresistance in cohorts of ovarian cancer tumours reveals correlations that support a role for these genes in vitro and in vivo. Here we show that miR-31 and KCNMA1 are involved in mediating cisplatin resistance in ovarian cancer. Our data gives a new insight into the potential mechanisms to therapeutically target in cisplatin resistance common to ovarian cancer.
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
authors.forename: Priya
authors.initials: P
authors.lastname: Samuel
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
authors.forename: Ryan Charles
authors.initials: RC
authors.lastname: Pink
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.|Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
authors.forename: Daniel Paul
authors.initials: DP
authors.lastname: Caley
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
authors.forename: James Michael Stevenson
authors.initials: JM
authors.lastname: Currie
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK.
authors.forename: Susan Ann
authors.initials: SA
authors.lastname: Brooks
authors.affiliation: Department of Biological and Medical Sciences, Faculty of Health and Life Sciences, Oxford Brookes University, Gipsy Lane, Oxford, OX3 0BP, UK. dcarter@brookes.ac.uk.
authors.forename: David Raul Francisco
authors.initials: DR
authors.lastname: Carter
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; C534612:MIRN31 microRNA, human; D035683:MicroRNAs; D002945:Cisplatin
keywords: BK channel; Cisplatin resistance; KCNMA1; Ovarian cancer; miR-31; miRNA