Nova Medical School (NMS), Universidade Nova de Lisboa/Faculty of Medical Sciences, New University of Lisbon, Lisbon, Portugal
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Type: Original Article
Title: Tumour suppressor microRNAs modulate drug resistance in malignant pleural mesothelioma by targeting
Authors: Glen Reid
Affiliations: The University of Otago in New Zealand
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.
Drug-resistant MPM cell lines exhibited reduced expression of tumour suppressor microRNAs. Restoration of microRNA expression sensitised both drug resistant and parental cell lines to chemotherapeutic agents and increased levels of drug-induced apoptosis. Taken together, this data suggests that miR-15a/16-1 and miR-34a are involved in the acquired and intrinsic drug resistance phenotype of MPM cells in part by modulation of the apoptotic response via targeting
Title: The role of exosomal microRNAs, focus on clinical applications of breast cancer
Authors: Aiko Sueta, Yutaka Yamamoto, Hirotaka Iwase
Affiliations: Department of Breast and Endocrine Surgery, Kumamoto University Graduate School of Medical Sciences
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.