Tang Yuhui, Zhao Baiwei, Wang Wanchuan, Chen Haoming, Zhang Junsheng, Xie Yi, Chen Yongming, Lin Feizhi, Li Yuanfang, Zhai Xiaohui, Zhou Wen
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
The Sixth Affiliated Hospital, South China University of Technology, Foshan, 528000, P. R. China.
Mol Cancer. 2025 Jun 6;24(1):165. doi: 10.1186/s12943-025-02341-7.
BACKGROUND: Long non-coding RNAs (lncRNAs) are essential modulators in tumor progression. While fatty acid (FA) metabolism can potentiate tumorigenesis, colonization, and metastasis, the roles of lncRNAs in reprograming FA metabolism and regulating gastric cancer (GC) metastasis remain elusive. METHODS: Whole RNA-sequencing and in silico analyses were conducted to identify clinically significant lncRNAs involved in GC metastasis. Among the identified lncRNAs, we focused on the novel lncRNA TENM3-AS1. RT-qPCR and FISH analyses revealed an increased expression of TENM3-AS1 in GC cell lines and patients. In vitro and in vivo functional experiments validated the effects of TENM3-AS1 to GC metastasis and the reprogramming of FA metabolism. ChIP, Biotinylated RNA pull-down, RIP, CHX-chase assay, ubiquitination assay, and RNA stabilization assay were employed to perceive the mechanisms underlying the effects of TENM3-AS1 in GC cells. RESULTS: TENM3-AS1 expression was significantly elevated in metastatic tumors and advanced primary tumors of GC patients. This increased expression was also associated with a worsened overall survival and progression-free survival. Functionally, TENM3-AS1 enhanced the migration and invasiveness of GC cells in vitro, promoted tumorigenesis and liver metastasis in vivo, and increased FA biosynthesis in GC cells. Mechanistically, our studies showed that the transcription factor EGR1 activated TENM3-AS1, which in turn upregulated the expression of FASN and hnRNPK. Furthermore, TENM3-AS1 interacted with and stabilized hnRNPK by increasing its deubiquitination. This interaction reprogrammed FA metabolism and promoted GC progression by increasing FASN mRNA stability through hnRNPK. CONCLUSIONS: In this study, by comparing lncRNA sequencing data from paired primary and peritoneal metastatic tumors and public transcriptome data from non-metastatic and metastatic samples, we clarified a novel lncRNA, TENM3-AS1. It was found that TENM3-AS1 was aberrantly activated in metastatic and advanced primary tumors, and was strongly correlated with a shorter survival in GC patients. Our study reveals the EGR1/TENM3-AS1/ hnRNPK/FASN axis as a novel curative target in metastatic GC.
背景：长链非编码RNA（lncRNAs）是肿瘤进展中的重要调节因子。虽然脂肪酸（FA）代谢可促进肿瘤发生、定植和转移，但lncRNAs在重编程FA代谢及调节胃癌（GC）转移中的作用仍不清楚。 方法：进行全RNA测序和计算机分析以鉴定参与GC转移的具有临床意义的lncRNAs。在鉴定出的lncRNAs中，我们聚焦于新型lncRNA TENM3-AS1。RT-qPCR和FISH分析显示TENM3-AS1在GC细胞系和患者中表达增加。体外和体内功能实验验证了TENM3-AS1对GC转移及FA代谢重编程的影响。采用染色质免疫沉淀、生物素化RNA下拉、RNA免疫沉淀、环己酰亚胺追踪实验、泛素化实验和RNA稳定性实验来探究TENM3-AS1在GC细胞中发挥作用的机制。 结果：TENM3-AS1表达在GC患者的转移瘤和晚期原发性肿瘤中显著升高。这种表达增加还与总体生存期和无进展生存期恶化相关。在功能上，TENM3-AS1在体外增强了GC细胞的迁移和侵袭能力，在体内促进了肿瘤发生和肝转移，并增加了GC细胞中的FA生物合成。在机制上，我们的研究表明转录因子EGR1激活了TENM3-AS1，进而上调了FASN和hnRNPK的表达。此外，TENM3-AS1通过增加hnRNPK的去泛素化与hnRNPK相互作用并使其稳定。这种相互作用通过hnRNPK增加FASN mRNA稳定性来重编程FA代谢并促进GC进展。 结论：在本研究中，通过比较配对的原发性和腹膜转移瘤的lncRNA测序数据以及非转移和转移样本的公共转录组数据，我们阐明了一种新型lncRNA，即TENM3-AS1。发现TENM3-AS1在转移瘤和晚期原发性肿瘤中异常激活，并且与GC患者较短的生存期密切相关。我们的研究揭示了EGR1/TENM3-AS1/hnRNPK/FASN轴是转移性GC的一个新的治疗靶点。
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