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

Our plain-English summary of Tumour suppressor microRNAs contribute to drug resistance in malignant pleural mesothelioma by targeting anti-apoptotic pathways, by M. Williams, Y.Y. Cheng, M. Phimmachanh, et al (Cancer Drug Resistance, 2019).

The study

• Authors: M. Williams, Y.Y. Cheng, M. Phimmachanh, P. Winata, N. van Zandwijk, G. Reid
• Journal: Cancer Drug Resistance
• Published: 2019;2(4):1193-1206
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© The Author(s) 2019.

In plain English

This laboratory study, with no patients or asbestos exposure, used one human malignant pleural mesothelioma (MPM) cell line, MSTO-211H. The authors grew sub-lines resistant to the chemotherapy drugs cisplatin, gemcitabine or vinorelbine. These were 2.5-fold, 6-fold and 2-fold more resistant than the original cells. All three resistant lines had lower levels of the microRNAs (small gene-silencing molecules) miR-15a, miR-16 and miR-34a. Lab-made copies of miR-15a or miR-16 made cells more sensitive to all three drugs. The article's abstract says miR-34a helped only with cisplatin and vinorelbine; its Results say all three microRNAs helped with all three drugs. Cisplatin and vinorelbine resistance was completely reversed; gemcitabine resistance only partly. The microRNAs increased drug-induced cell death and lowered BCL2, a protein that helps cells survive. Blocking BCL2 directly only modestly increased sensitivity to cisplatin and vinorelbine, and did not change gemcitabine sensitivity. One Results passage says this was seen only in the resistant lines; other passages also describe a vinorelbine effect in the original cells. The authors concluded these microRNAs can make MPM cell lines more sensitive to these drugs, partly through BCL2, with other targets likely involved.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) cell-line experiment
• Who was studied: One human malignant pleural mesothelioma cell line, MSTO-211H, obtained from the ATCC, plus sub-lines made resistant to cisplatin, gemcitabine or vinorelbine; no human participants
• Exposure: Not an asbestos exposure study. Cells were given synthetic copies (mimics) of miR-15a, miR-16 or miR-34a, or siRNAs that block BCL2, and were then treated with cisplatin, gemcitabine or vinorelbine.
• Main results:
  • Compared with the original (parental) cells, the cisplatin-resistant line was 2.5-fold more resistant, the vinorelbine-resistant line 2-fold and the gemcitabine-resistant line 6-fold
  • In the gemcitabine-resistant line, miR-15a was reduced 2.6-fold and miR-34a 2.1-fold. In the vinorelbine-resistant line, miR-15a was reduced 2.8-fold and miR-34a 3-fold.
  • miR-16 levels were low in all three drug-resistant lines compared with the parental line
  • The abstract within the article reports that miR-15a or miR-16 mimics reversed resistance to all three drugs, while miR-34a reversed only cisplatin and vinorelbine resistance
  • The Results section, by contrast, states that all three microRNAs reduced resistance to all three drugs
  • After microRNA mimic transfection, resistance to cisplatin and vinorelbine in the drug-selected lines was completely reversed
  • Gemcitabine resistance was only partly reversed by the microRNA mimics, and the cells stayed slightly less sensitive than the parental line
  • With vinorelbine, markers of late apoptotic cell death rose about 7-fold in the vinorelbine-resistant cells and about 4-fold in the parental cells after transfection with any of the three mimics
  • All three mimics reduced BCL2 mRNA and protein in both parental and resistant cell lines
  • Luciferase assays showed that miR-15a and miR-16 both interact with the 3' UTR region of the BCL2 mRNA
  • Blocking BCL2 directly with siRNAs caused only a modest increase in sensitivity to vinorelbine and cisplatin and no change for gemcitabine
  • One Results sentence states that the increased sensitivity to cisplatin and vinorelbine after BCL2 blocking was seen only in the resistant line, not in the parental line
  • Another Results sentence states that vinorelbine sensitivity changed after BCL2 blocking in both the vinorelbine-resistant and the parental cells
  • The Discussion states that the parental line showed no shift in cisplatin or gemcitabine sensitivity after BCL2 blocking
• The authors' conclusion: The authors concluded that tumour suppressor microRNAs can make MPM cell lines more sensitive to clinically used chemotherapy drugs. They attributed this partly to BCL2, but because blocking BCL2 alone did not reproduce the full effect, they considered it highly likely that other targets are involved.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Gemcitabine, Vinorelbine, Apoptosis.

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