Department of Gynecology, The Second Hospital of Jilin University, Changchun, China.
Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, China.
J Cell Physiol. 2019 Nov;234(11):21126-21134. doi: 10.1002/jcp.28715. Epub 2019 Apr 29.
c-Myb regulates tumorigenesis in multiple cancers. Here we show, for the first time, the mechanism of c-Myb-mediated proliferation, invasion, and drug resistance in ovarian cancer (OC), the most lethal gynecological cancer, and a comparative analyses of dietary agents, curcumin, epigallocatechin-3-gallate (EGCG), and sulforaphane in inhibiting c-Myb activity. We evaluated myb expression in patients with OC and found its increased expression in patients with cancer, compared with normal controls and in higher grade tumors, compared with low-grade tumors. Using ES2 and OVCAR3 cell line models, along with the silencing or overexpression of c-Myb, we establish a role of c-Myb in determining resistance to cisplatin. c-Myb overexpression activated NF-κB and STAT3 signaling leading to enhanced proliferation, invasion, and cisplatin resistance. Contrary to this, silencing of c-Myb inhibited proliferation, invasion, and sensitized OC cells to cisplatin. Further, among the dietary agents tested, EGCG almost completely inhibited the c-Myb-induced proliferation and invasion whereas sulforaphane also had significant inhibitory effect. Both compounds significantly sensitized OC cells to cisplatin, reversing the c-Myb effects. Higher c-Myb levels in patients with ovarian cancer lead to poor survival and our results indicate a possible effect of dietary factors EGCG and sulforaphane against c-Myb-mediated ovarian cancer progression and chemoresistance.
c-Myb 在多种癌症中调节肿瘤发生。在这里，我们首次展示了 c-Myb 介导的增殖、侵袭和耐药性在卵巢癌（OC）中的作用机制，OC 是最致命的妇科癌症，并且对膳食因子姜黄素、表没食子儿茶素没食子酸酯 (EGCG) 和萝卜硫素进行了比较分析，以抑制 c-Myb 活性。我们评估了 OC 患者中 myb 的表达情况，并发现与正常对照组相比，癌症患者的表达增加，与低级别肿瘤相比，高级别肿瘤的表达增加。使用 ES2 和 OVCAR3 细胞系模型，以及 c-Myb 的沉默或过表达，我们确定了 c-Myb 在决定对顺铂耐药中的作用。c-Myb 的过表达激活了 NF-κB 和 STAT3 信号通路，导致增殖、侵袭和对顺铂的耐药性增强。与此相反，c-Myb 的沉默抑制了增殖、侵袭，并使 OC 细胞对顺铂敏感。此外，在所测试的膳食因子中，EGCG 几乎完全抑制了由 c-Myb 诱导的增殖和侵袭，而萝卜硫素也具有显著的抑制作用。这两种化合物都显著提高了 OC 细胞对顺铂的敏感性，从而逆转了 c-Myb 的作用。卵巢癌患者中更高的 c-Myb 水平导致预后不良，我们的结果表明膳食因子 EGCG 和萝卜硫素可能对 c-Myb 介导的卵巢癌进展和化疗耐药有一定的作用。
