School of Nursing, Jilin University, Changchun, Jilin, 130021, China.
Department of Radiotherapy, Second Hospital of Jilin University, Changchun, 130022, Jilin, China.
Sci Rep. 2020 Apr 23;10(1):6893. doi: 10.1038/s41598-020-63396-8.
c-MYB has been reported to be elevated in few cancers, including in ovarian cancer. It influences resistance to cisplatin but the details are not very well understood. The objective of this study was to further evaluate role of c-MYB in ovarian cancer's cisplatin resistance. To elucidate the underlying mechanism of cisplatin resistance in ovarian cancer, we focused on the epigenetic regulation by miRNAs. Two cell lines, ES2 and OVCAR3, were used as the model systems. C-MYB expression was either up-regulated or silenced and the resulting effect on cisplatin resistance evaluated, along with the mechanistic role of miR-21, through transfections with pre/anti-miRNAs. An in vivo cisplatin resistance model was also employed to verify findings. High c-MYB correlated with increased miR-21. High c-MYB also resulted in induction of EMT and increased resistance against cisplatin which was attenuated by anti-miR-200s. c-MYB decreased β-catenin phosphorylation and thus activated wnt signaling. Silencing of c-MYB resulted in reduced miR-21 levels, reduced EMT, reduced cisplatin IC-50s and increased β-catenin phosphorylation. In an in vivo mice model of cisplatin resistance, c-MYB overexpressing ES2 xenografts were more aggressive than their control counterparts. These c-MYB overexpressing ES xenografts were significantly more resistant to cisplatin but could be sensitized to cisplatin by anti-miR-21. Our results provide a novel mechanism of cisplatin resistance by c-MYB which involves an essential role of miR-21.
c-MYB 在少数癌症中被报道升高，包括卵巢癌。它影响顺铂耐药，但细节尚不清楚。本研究的目的是进一步评估 c-MYB 在卵巢癌顺铂耐药中的作用。为了阐明卵巢癌顺铂耐药的潜在机制，我们专注于 miRNA 的表观遗传调控。使用 ES2 和 OVCAR3 两个细胞系作为模型系统。c-MYB 的表达被上调或沉默，并评估其对顺铂耐药性的影响，同时通过 pre/anti-miRNAs 的转染研究 miR-21 的机制作用。还采用体内顺铂耐药模型来验证研究结果。高 c-MYB 与 miR-21 增加相关。高 c-MYB 还导致 EMT 的诱导和对顺铂的耐药性增加，这可以通过抗 miR-200 减弱。c-MYB 降低β-连环蛋白磷酸化，从而激活 wnt 信号。沉默 c-MYB 导致 miR-21 水平降低、EMT 减少、顺铂 IC50 降低和β-连环蛋白磷酸化增加。在体内顺铂耐药的小鼠模型中，c-MYB 过表达的 ES2 异种移植瘤比对照更具侵袭性。这些 c-MYB 过表达的 ES 异种移植瘤对顺铂的耐药性明显增加，但可以通过抗 miR-21 使顺铂敏感。我们的研究结果提供了 c-MYB 引起顺铂耐药的新机制，该机制涉及 miR-21 的重要作用。
