MGH/MIT/HMS Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA.
Sci Rep. 2020 Feb 6;10(1):1970. doi: 10.1038/s41598-020-58919-2.
Chemotherapy, a major cancer treatment approach, suffers seriously from multidrug resistance (MDR), generally caused by innate DNA repair proteins that reverse the DNA modification by anti-cancer therapeutics or trans-membrane efflux proteins that pump anti-cancer therapeutics out of the cytosol. This project focused on finding microRNAs that can regulate MDR proteins by managing corresponding mRNA levels through post-transcriptional regulation based on nucleotide sequence matching. Screening was done with bioinformatics databases for unpublished/unexplored microRNAs with high nucleotide sequence correspondence to two representative MDR proteins, MGMT (a DNA repair protein) and ABCB1 (an efflux protein), revealing microRNA-4539 and microRNA-4261 respectively. To investigate the enhancement of chemotherapeutics in cancer cells, high MGMT expressing glioblastoma (T98G) and a high ABCB1 expressing triple-negative breast cancer cell line (MDA-MB-231-luc) were treated with varying concentrations of chemotherapeutics and corresponding miRNAs. Newly identified MDR-related miRNAs (MDRmiRs) enhanced the response to anti-cancer therapeutics and resulted in effective cell death. In this study, we demonstrated that therapeutic miRNAs could be identified based on the nucleotide sequence matching of miRNAs to targeted mRNA and the same approach could be employed for the screening of therapeutic candidates to regulate specific target proteins in diverse diseases.
化疗是一种主要的癌症治疗方法，但严重受到多药耐药性（MDR）的影响，MDR 通常是由内在的 DNA 修复蛋白引起的，这些蛋白可以逆转抗癌治疗药物引起的 DNA 修饰，或者通过跨膜外排蛋白将抗癌治疗药物泵出细胞质。本项目专注于寻找可以通过基于核苷酸序列匹配的转录后调控来调节 MDR 蛋白的 microRNAs，从而管理相应的 mRNA 水平。通过生物信息学数据库筛选具有高核苷酸序列对应性的未发表/未探索的 microRNAs，这些 microRNAs 对应两个代表性的 MDR 蛋白，MGMT（一种 DNA 修复蛋白）和 ABCB1（一种外排蛋白），分别揭示了 microRNA-4539 和 microRNA-4261。为了研究增强癌症细胞中的化疗药物效果，用不同浓度的化疗药物和相应的 microRNAs 处理高表达 MGMT 的神经胶质瘤（T98G）和高表达 ABCB1 的三阴性乳腺癌细胞系（MDA-MB-231-luc）。新发现的与 MDR 相关的 microRNAs（MDRmiRs）增强了对抗癌治疗药物的反应，导致有效的细胞死亡。在这项研究中，我们证明了可以基于 microRNA 与靶向 mRNA 的核苷酸序列匹配来鉴定治疗性 microRNAs，并且可以采用相同的方法筛选治疗候选物来调节不同疾病中的特定靶蛋白。
