Sun Yat-sen University Cancer Center, the State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Center for Precision Medicine of Sun Yat-sen University, Guangzhou, P.R. China.
Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China.
Clin Cancer Res. 2022 Oct 14;28(20):4521-4535. doi: 10.1158/1078-0432.CCR-22-0991.
Cisplatin-based chemotherapy effectively improves the distant-metastasis control in nasopharyngeal carcinoma (NPC), but approximately 30% of patients develop treatment failure due to chemoresistance. However, the underlying mechanisms remain poorly understood.
Circular RNA (circRNA) sequencing data were used to identify metastasis-specific circRNAs and the expression of circIPO7 was validated in NPC tissues as well as NPC cell lines by qRT-PCR. The whole transcriptional profile upon circIPO7 knockdown was applied to explore the biological function and regulatory mechanism, which were further confirmed by in vitro and in vivo metastasis/chemosensitivity assays. We also evaluated the value of circIPO7 expression in predicting NPC metastasis and cisplatin chemoresistance by analyzing a cohort of 183 NPC patients.
In this study, circIPO7, a novel circRNA, is found to be specifically overexpressed in NPC patients with distant metastasis. Knockdown of circIPO7 in NPC cells suppresses their metastasis and increases sensitivity to cisplatin treatment in vitro and in vivo. Mechanistically, circIPO7 binds to Y-box binding protein-1 (YBX1) protein in the cytoplasm and facilitates its phosphorylation at serine 102 (p-YBX1S102) by the kinase AKT, which further promotes YBX1 nuclear translocation and activates FGFR1, TNC, and NTRK1 transcription. Clinically, higher circIPO7 expression indicates unfavorable distant metastasis-free survival in NPC patients given cisplatin-based chemotherapy.
Altogether, this study identifies oncogenic circIPO7 as a prognostic marker after cisplatin-based chemotherapy and as a potential therapeutic target for overcoming metastasis and chemoresistance in NPC.
基于顺铂的化疗可有效改善鼻咽癌（NPC）的远处转移控制，但约 30%的患者因化疗耐药而治疗失败。然而，其潜在机制仍知之甚少。
使用环状 RNA（circRNA）测序数据来鉴定转移特异性 circRNA，并通过 qRT-PCR 验证 circIPO7 在 NPC 组织和 NPC 细胞系中的表达。在 circIPO7 敲低后，进行全转录组分析以探索其生物学功能和调控机制，并通过体外和体内转移/化疗敏感性测定进一步验证。我们还通过分析 183 名 NPC 患者的队列来评估 circIPO7 表达在预测 NPC 转移和顺铂化疗耐药性方面的价值。
在这项研究中，发现一种新型环状 RNA circIPO7 在有远处转移的 NPC 患者中特异性过表达。在 NPC 细胞中敲低 circIPO7 可抑制其转移，并增加体外和体内对顺铂治疗的敏感性。在机制上，circIPO7 在细胞质中与 Y 框结合蛋白-1（YBX1）蛋白结合，并通过 AKT 激酶促进其丝氨酸 102 磷酸化（p-YBX1S102），进而促进 YBX1 核转位并激活 FGFR1、TNC 和 NTRK1 转录。临床上，circIPO7 表达较高的 NPC 患者接受基于顺铂的化疗后，无远处转移生存预后较差。
总之，本研究确定致癌性 circIPO7 是基于顺铂化疗后的预后标志物，也是克服 NPC 转移和化疗耐药的潜在治疗靶点。
