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

Marissa Williams; Yuen Yee Cheng; Monica Phimmachanh; Patrick Winata; Nico van Zandwijk; Glen Reid

doi:10.20517/cdr.2019.41

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

Cancer Drug Resist. 2019 Dec 19;2(4):1193-1206. doi: 10.20517/cdr.2019.41. eCollection 2019.

Authors

Marissa Williams^{1

2}, Yuen Yee Cheng^{1

2}, Monica Phimmachanh^{1

2

3}, Patrick Winata^{1

2}, Nico van Zandwijk^{1

2

4}, Glen Reid^{1

2

5}

Affiliations

¹ Asbestos Diseases Research Institute, Sydney NSW2139, Australia.
² Sydney Medical School, The University of Sydney, Sydney NSW2050, Australia.
³ Current address: Garvan Institute of Medical Research, Darlinghurst, Sydney NSW2010, Australia.
⁴ Current address: Sydney Local Health District, Concord, Sydney NSW2194, Australia.
⁵ Current address: Department of Pathology, University of Otago, Dunedin 9016, New Zealand.

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.

Keywords: BCL2; Malignant pleural mesothelioma; apoptosis; miR-15a; miR-16; miR-34a.