Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer
Retinoic Acid-Related Orphan Receptor C Regulates Proliferation, Glycolysis, and Chemoresistance via the PD-L1/ITGB6/STAT3 Signaling Axis in Bladder Cancer
复制标题
视黄酸相关孤儿受体 C 通过 PD-L1/ITGB6/STAT3 信号轴调节膀胱癌的增殖、糖酵解和化疗耐药
DOI：
10.1158/0008-5472.can-18-3842
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发表时间：
2019-05-15
期刊：
影响因子：
11.2
通讯作者：
Wang, Ziliang
中科院分区：
文献类型：
--
作者：
Cao, Dalong;Qi, Zihao;Wang, Ziliang
视黄酸相关孤儿受体 C (RORC) 是核孤儿受体家族的一员，在多种恶性肿瘤的细胞增殖、转移和化疗耐药中发挥重要的调节功能。在这里，我们发现膀胱癌患者的肿瘤组织中 RORC 表达缺失。 RORC 表达增强可抑制细胞增殖和葡萄糖代谢，并增加顺铂诱导的体外和体内细胞凋亡。 RORC 结合程序性死亡配体 1 (PD-L1) 的启动子区域并负向调节 PD-L1 的表达。 PD-L1直接与整合素β6（ITGB6）相互作用并激活ITGB6/FAK信号通路。 RORC通过抑制PD-L1/ITGB6信号通路阻止STAT3的核转位，从而进一步抑制膀胱细胞增殖和葡萄糖代谢并增加顺铂诱导的细胞凋亡。这些发现表明，RORC 通过参与 PD-L1/ITGB6/STAT3 信号轴来调节膀胱癌细胞增殖、葡萄糖代谢和化疗耐药。此外，这种对PD-L1信号传导的新认识可能会指导治疗靶点的选择，以防止肿瘤复发。意义：这些发现表明膀胱癌中RORC介导的PD-L1/ITGB6/FAK/STAT3信号轴的调节提供了几个潜在的治疗靶点来预防肿瘤进展。
Retinoic acid-related orphan receptor C (RORC) is a member of the nuclear orphan receptor family and performs critical regulatory functions in cell proliferation, metastasis, and chemoresistance in various types of malignant tumors. Here we showed that expression of RORC is lost in tumor tissues of bladder cancer patients. Enhanced expression of RORC suppressed cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis in vitro and in vivo. RORC bound the promoter region of programmed death ligand-1 (PD-L1) and negatively regulated PD-L1 expression. PD-L1 directly interacted with integrin beta 6 (ITGB6) and activated the ITGB6/FAK signaling pathway. RORC prevented the nuclear translocation of STAT3 via suppression of the PD-L1/ITGB6 signaling pathway, which further inhibited bladder cell proliferation and glucose metabolism and increased cisplatin-induced apoptosis. These findings reveal that RORC regulates bladder cancer cell proliferation, glucose metabolism, and chemoresistance by participating in the PD-L1/ITGB6/STAT3 signaling axis. Moreover, this new understanding of PD-L1 signaling may guide the selection of therapeutic targets to prevent tumor recurrence.Significance: These findings suggest that RORC-mediated regulation of a PD-L1/ITGB6/FAK/STAT3 signaling axis in bladder cancer provides several potential therapeutic targets to prevent tumor progression.