Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways.

Marissa Williams,Nico Van Zandwijk,Glen Reid,Monica Phimmachanh,Yuen Yee Cheng,Patrick Winata

doi:10.20517/cdr.2019.41

Marissa Williams, Nico Van Zandwijk + Show 4 more

Open Access

https://doi.org/10.20517/cdr.2019.41

Copy DOI

Abstract

Aim: Aberrant microRNA expression is a common event in cancer drug resistance, however its involvement in malignant pleural mesothelioma (MPM) drug resistance is largely unexplored. We aimed to investigate the contribution of microRNAs to the resistance to drugs commonly used in the treatment of MPM.Methods: Drug resistant MPM cell lines were generated by treatment with cisplatin, gemcitabine or vinorelbine. Expression of microRNAs was quantified using RT-qPCR. Apoptosis and drug sensitivity assays were carried out following transfection with microRNA mimics or BCL2 siRNAs combined with drugs.Results: Expression of miR-15a, miR-16 and miR-34a was downregulated in MPM cells with acquired drug resistance. Transfection with miR-15a or miR-16 mimics reversed the resistance to cisplatin, gemcitabine or vinorelbine, whereas miR-34a reversed cisplatin and vinorelbine resistance only. Similarly, in parental cell lines, miR-15a or miR-16 mimics sensitised cells to all drugs, whereas miR-34a increased response to cisplatin and vinorelbine. Increased microRNA expression increased drug-induced apoptosis and caused BCL2 mRNA and protein reduction. RNAi-mediated knockdown of BCL2 partly recapitulated the increase in drug sensitivity in cisplatin and vinorelbine treated cells.Conclusion: Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs. Increasing tumour suppressor of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents, in part through targeting of BCL2. Taken together, these data suggest that miR-15a, miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells.

Highlights

malignant pleural mesothelioma (MPM) is an aggressive tumour caused by the inhalation of asbestos fibres[1]
These data suggest that miR-15a, miR-16 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells
To determine whether previously identified downregulated tumour suppressor miRNAs are involved in MPM drug resistance, we measured levels of miRNAs in MPM cell lines with acquired drug resistance to cisplatin (MSTO-CisR), vinorelbine (MSTO-VinoR) and gemcitabine (MSTO-GemR)

Summary

Introduction

MPM is an aggressive tumour caused by the inhalation of asbestos fibres[1]. The prognosis for MPM is extremely poor, which is mainly attributed to the tumour being inherently chemo-resistant resulting in poor response to available therapies[2,3,4]. Approximately 40% of patients will respond to the combined cisplatin and pemetrexed treatment regime, which results in a modest median survival of 12 months[2]. Response to agents routinely used in second- or third-line therapy, including gemcitabine and vinorelbine, is poor with less than 30% of patients demonstrating disease control after 3 months of treatment and median overall survival rates less that 6 months[5,6,7]. Uncovering the molecular pathways driving mechanisms of resistance and how they are regulated is necessary to identify new therapeutic targets and treatment approaches[4]

Objectives

Methods

Results

Discussion

Conclusion