Jia Guo-Dong, Xie Si-Yi, Li Xiao-Yun, Li Liang-Ji, Jin Jing, Liu Li-Ting, Sun Xue-Song, Liu Sai-Lan, Chen Qiu-Yan, Tang Lin-Quan, Yuan Li, Mai Hai-Qiang
Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Centre, State Key Laboratory of Oncology in South China, Collaborative Innovation Centre for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
J Exp Clin Cancer Res. 2025 Jul 31;44(1):223. doi: 10.1186/s13046-025-03468-7.
Nasopharyngeal carcinoma (NPC) is often diagnosed at an advanced stage due to its hidden location, with 70-80% of patients presenting with cervical lymph node metastasis. This high metastasis rate is a major cause of treatment failure and mortality. Non-coding RNAs, particularly circRNAs, have emerged as key players in tumor development, but their roles in NPC lymph node metastasis and angiogenesis remain unclear. This study aimed to identify key circRNAs involved in NPC lymph node metastasis and elucidate their mechanisms of action.
We identified circFAM13B, a differentially expressed circRNA, using transcriptome sequencing of nasopharyngeal tissues from patients with and without lymph node metastasis. Stable cell lines with circFAM13B overexpression and knockdown were constructed. Functional experiments, including cell invasion, migration, and metastasis assays, were performed in vitro and in vivo. Mechanistic studies involved RNA sequencing, RNA pull-down, and RNA immunoprecipitation assays to explore interacting proteins and signaling pathways.
CircFAM13B was downregulated in metastatic tissues and localized in the endoplasmic reticulum (ER). It acted as a tumor suppressor by binding to RBM3 and promoting degradation of uXBP1 mRNA, a key ER stress molecule. This interaction downregulated sXBP1 and CST6, inhibiting lymphangiogenesis and metastasis. Reduced CST6 expression was associated with poor prognosis in NPC.
Our study reveals that circFAM13B inhibits ER stress-related pathways in NPC, highlighting its potential as a therapeutic target for lymph node metastasis.
鼻咽癌（NPC）因其位置隐匿，常于晚期才被诊断出来，70%-80%的患者会出现颈部淋巴结转移。这种高转移率是治疗失败和死亡的主要原因。非编码RNA，尤其是环状RNA（circRNA），已成为肿瘤发展的关键因素，但其在鼻咽癌淋巴结转移和血管生成中的作用仍不清楚。本研究旨在鉴定参与鼻咽癌淋巴结转移的关键circRNA，并阐明其作用机制。
我们通过对有或无淋巴结转移的鼻咽癌患者鼻咽组织进行转录组测序，鉴定出差异表达的circRNA——circFAM13B。构建了circFAM13B过表达和敲低的稳定细胞系。在体外和体内进行了包括细胞侵袭、迁移和转移分析在内的功能实验。机制研究涉及RNA测序、RNA下拉和RNA免疫沉淀分析，以探索相互作用的蛋白质和信号通路。
circFAM13B在转移组织中表达下调，定位于内质网（ER）。它通过与RBM3结合并促进关键内质网应激分子uXBP1 mRNA的降解，发挥肿瘤抑制作用。这种相互作用下调了sXBP1和CST6，抑制淋巴管生成和转移。CST6表达降低与鼻咽癌患者的不良预后相关。
我们的研究表明，circFAM13B抑制鼻咽癌中内质网应激相关通路，凸显了其作为淋巴结转移治疗靶点的潜力。
