Department of Systems Biology, Division of Basic Science Research, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
MicroRNAs (miRNAs) have been identified to be key players in health and disease which are deregulated in cancer which can influence the development of resistance to treatment. This special issue summarizes recent advances on the impact of miRNAs on therapy resistance in cancer and highlights how miRNA expression profiles can predict clinical outcome in cancer. Finally, we will provide an overview of the challenges of miRNA-targeted therapies for reversing drug resistance to sensitize tumor cells to chemotherapy, radiotherapy, and targeted treatment.
Malignant Pleural mesothelioma (MPM) is an aggressive thoracic malignancy with limited treatment options. MPM has a poor prognosis, predominately due to its inherent drug resistance and its limited response to current therapies. Aberrant microRNA expression is a common event in cancer with many implicated in chemo-resistance, however the role of microRNAs in MPM drug resistance is largely unexplored.
MPM cell lines with acquired drug resistance to cisplatin, gemcitabine and vinorelbine were generated by periodic treatment with the IC50 of each chemotherapeutic agent. Expression levels of mature microRNAs were compared between parental MPM cell lines and cell lines with acquired drug resistance using RT-qPCR. Apoptosis and drug sensitivity assays were carried out following reversetransfection with microRNA mimics and Bcl-2 siRNAs combined with cisplatin, gemcitabine and vinorelbine treatment. Levels of apoptosis and necrosis were determined by PI and annexin V staining while Bcl-2 mRNA and protein expression was determined by RT-qPCR and Western blotting respectively.
Expression of miR-15a/16-1 and miR-34a was downregulated in MPM cells with acquired resistance to cisplatin, gemcitabine and vinorelbine, compared to the parental counterpart. Transfection with mimics corresponding to miR-15a and miR-16 were most effective in increasing sensitivity to all chemotherapeutics tested in drug resistant cell lines. In parental cell lines, miR-15a or miR-16 mimicinduced sensitisation to all drugs was observed, with restoration of miR-34a or miR-34b capable of increasing response to cisplatin and vinorelbine. Elevated miR-15/16 and miR-34a expression sensitised both parental and resistant cell lines to cisplatin, gemcitabine and vinorelbine-induced apoptosis, and caused Bcl-2 mRNA and protein reduction. Furthermore, siRNA induced knockdown of Bcl-2 also induced a modest improvement in drug sensitivity.
Abstract: Despite several advances in targeted therapies for breast cancer, breast-cancer-associated death remains high in women. It is partially due to the lack of reliable markers predicting metastatic disease or recurrence after initial therapy. Recent research in clinical validity of circulating cancer-specific biomarkers as a ‘liquid biopsy’ is of growing interest. Of these, exosomal microRNAs (miRNAs) are promising candidate biomarkers for clinical use of breast cancer. In addition to the diagnostic values, exosomal miRNAs play important role in predicting clinical outcome or treatment response. In this review, we focused on the findings of exosomal miRNAs related to disease detection, prognostic impact and therapeutic effect for breast cancer and discuss their clinical utility.