School of Nursing, Jilin University, Changchun, 130021, Jilin, China.
Department of Neurology, Second Hospital of Jilin University, Changchun, 130022, Jilin, China.
J Ovarian Res. 2024 May 14;17(1):102. doi: 10.1186/s13048-024-01429-w.
Ovarian cancer is a major gynecological cancer that has poor prognosis associated mainly to its late diagnosis. Cisplatin is an FDA approved ovarian cancer therapy and even though the therapy is initially promising, the patients mostly progress to resistance against cisplatin. The underlying mechanisms are complex and not very clearly understood. Using two different paired cell lines representing cisplatin-sensitive and the cisplatin-resistant ovarian cancer cells, the ES2 and the A2780 parental and cisplatin-resistant cells, we show an elevated proto-oncogene c-Myb in resistant cells. We further show down-regulated lncRNA NKILA in resistant cells with its de-repression in resistant cells when c-Myb is silenced. NKILA negatively correlates with cancer cell and invasion but has no effect on cellular proliferation or cell cycle. C-Myb activates NF-κB signaling which is inhibited by NKILA. The cisplatin resistant cells are also marked by upregulated stem cell markers, particularly LIN28A and OCT4, and downregulated LIN28A-targeted let-7 family miRNAs. Whereas LIN28A and downregulated let-7s individually de-repress c-Myb-mediated cisplatin resistance, the ectopic expression of let-7s attenuates LIN28A effects, thus underlying a c-Myb-NKILA-LIN28A-let-7 axis in cisplatin resistance of ovarian cancer cells that needs to be further explored for therapeutic intervention.
卵巢癌是一种主要的妇科癌症，其预后较差，主要与晚期诊断有关。顺铂是一种获得 FDA 批准的卵巢癌治疗药物，尽管该治疗方法最初很有希望，但患者大多对顺铂产生耐药性。其潜在机制复杂，尚未得到充分理解。我们使用两种不同的配对细胞系，代表顺铂敏感和顺铂耐药的卵巢癌细胞，ES2 和 A2780 亲本和顺铂耐药细胞，显示耐药细胞中原癌基因 c-Myb 升高。我们进一步显示，lncRNA NKILA 在耐药细胞中下调，而当 c-Myb 沉默时，其在耐药细胞中去抑制。NKILA 与癌细胞和侵袭呈负相关，但对细胞增殖或细胞周期没有影响。c-Myb 激活 NF-κB 信号通路，而 NKILA 抑制该信号通路。顺铂耐药细胞还表现出上调的干细胞标志物，特别是 LIN28A 和 OCT4，以及下调的 LIN28A 靶向 let-7 家族 miRNA。虽然 LIN28A 和下调的 let-7s 单独去抑制 c-Myb 介导的顺铂耐药性，但 let-7s 的异位表达减弱了 LIN28A 的作用，因此在卵巢癌细胞的顺铂耐药性中存在 c-Myb-NKILA-LIN28A-let-7 轴，需要进一步探索用于治疗干预。
