Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling
Loss of RBMS3 Confers Platinum Resistance in Epithelial Ovarian Cancer via Activation of miR-126-5p/β-catenin/CBP signaling
复制标题
RBMS3 缺失通过激活 miR-126-5p/β-catenin/CBP 信号通路赋予上皮性卵巢癌铂类耐药性
DOI：
10.1158/1078-0432.ccr-18-2554
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发表时间：
2019-02-01
影响因子：
11.5
通讯作者：
Li, Jun
中科院分区：
文献类型：
--
作者：
Wu, Geyan;Cao, Lixue;Li, Jun
目的：对铂类化疗药物的耐药是肿瘤治疗中难以克服的障碍，并导致肿瘤复发。本研究旨在探讨RBMS 3基因缺失诱导卵巢上皮性癌（epithelial ovarian cancer，EOC）化疗耐药的机制。实验设计：采用荧光原位杂交（FISH）和免疫组化（IHC）技术检测15例临床EOC组织和150例临床病理标本中RBMS 3基因的缺失频率和表达。通过体外克隆形成和Annexin V测定以及体内腹腔内肿瘤模型检测RBMS 3缺失和CBP/β-catenin拮抗剂PRI-724对化疗耐药性的影响。使用CLIP-seq、RIP、电泳迁移率变动以及免疫印迹和免疫荧光分析探讨了RBMS 3缺失持续激活miR-126 - 5 p/β-连环蛋白/CBP信号传导的机制以及RBMS 3和miR 126 - 5 p竞争性调节DKK 3、AXIN 1、BACH 1和NFAT 5的作用。结果：EOC中RBMS 3的缺失与总体生存期和无复发生存期相关。RBMS 3的基因缺失显着增强了EOC细胞在体外和体内的耐药性，而RBMS 3的恢复则降低了EOC细胞的耐药性。RBMS 3通过竞争性阻止miR-126- 5 p介导的对这些转录物的抑制，直接与多种负调节因子（包括DKK 3、AXIN 1、BACH 1和NFAT 5）结合并稳定这些负调节因子，从而抑制β-连环蛋白/CBP信号传导。重要的是，CBP/β-catenin拮抗剂PRI-724的联合治疗诱导RBMS 3缺失的EOC对platinum therapy.Conclusions的敏感性：我们的研究结果表明，基因消融RBMS 3有助于化疗耐药性和PRI-724可能作为一个潜在的定制治疗RBMS 3缺失的EOC患者。
Purpose: The development of resistance to platinum-based chemotherapy remains the unsurmountable obstacle in cancer treatment and consequently leads to tumor relapse. This study aims to investigate the mechanism by which loss of RBMS3 induced chemoresistance in epithelial ovarian cancer (EOC).Experimental Design: FISH and IHC were used to determine deletion frequency and expression of RBMS3 in 15 clinical EOC tissues and 150 clinicopathologically characterized EOC specimens. The effects of RBMS3 deletion and CBP/beta-catenin antagonist PRI-724 in chemoresistance were examined by clone formation and Annexin V assays in vitro, and by intraperitoneal tumor model in vivo. Themechanism by which RBMS3 loss sustained activation of miR-126-5p/beta-catenin/CBP signaling and the effects of RBMS3 and miR126- 5p competitively regulatingDKK3, AXIN1, BACH1, and NFAT5 was explored using CLIP-seq, RIP, electrophoretic mobility shift, and immunoblotting and immunofluorescence assays.Results: Loss of RBMS3 in EOC was correlated with the overall and relapse-free survival. Genetic ablation of RBMS3 significantly enhanced, whereas restoration of RBMS3 reduced, the chemoresistance ability of EOC cells both in vitro and in vivo. RBMS3 inhibited beta-catenin/CBP signaling through directly associating with and stabilizing multiple negative regulators, including DKK3, AXIN1, BACH1, and NFAT5, via competitively preventing the miR-126-5p-mediated repression of these transcripts. Importantly, cotherapy of CBP/beta-catenin antagonist PRI-724 induced sensitization of RBMS3-deleted EOC to platinum therapy.Conclusions: Our results demonstrate that genetic ablation of RBMS3 contributes to chemoresistance and PRI-724 may serve as a potential tailored treatment for patients with RBMS3-deleted EOC.