egr1介导的lncRNA TENM3-AS1通过重编程脂肪酸代谢增强胃癌转移

IF 33.9 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-06-06 DOI:10.1186/s12943-025-02341-7

Yuhui Tang, Baiwei Zhao, Wanchuan Wang, Haoming Chen, Junsheng Zhang, Yi Xie, Yongming Chen, Feizhi Lin, Yuanfang Li, Xiaohui Zhai, Wen Zhou

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引用次数: 0

摘要

长链非编码rna （lncRNAs）是肿瘤进展的重要调节因子。虽然脂肪酸（FA）代谢可以促进肿瘤的发生、定植和转移，但lncrna在重编程FA代谢和调节胃癌（GC）转移中的作用尚不清楚。我们进行了全rna测序和计算机分析，以鉴定与胃癌转移有关的具有临床意义的lncrna。在已鉴定的lncRNA中，我们重点研究了新型lncRNA TENM3-AS1。RT-qPCR和FISH分析显示，TENM3-AS1在胃癌细胞系和患者中的表达增加。体外和体内功能实验验证了TENM3-AS1对胃癌转移和FA代谢重编程的影响。采用ChIP、生物素化RNA拉下、RIP、CHX-chase实验、泛素化实验和RNA稳定实验来了解TENM3-AS1在GC细胞中的作用机制。胃癌患者的转移性肿瘤和晚期原发肿瘤中TENM3-AS1表达明显升高。这种增加的表达也与总生存期和无进展生存期的恶化有关。在功能上，TENM3-AS1在体外增强胃癌细胞的迁移和侵袭性，在体内促进肿瘤发生和肝转移，增加胃癌细胞FA的生物合成。在机制上，我们的研究表明转录因子EGR1激活TENM3-AS1，进而上调FASN和hnRNPK的表达。此外，TENM3-AS1通过增加hnRNPK的去泛素化，与hnRNPK相互作用并稳定hnRNPK。这种相互作用通过hnRNPK增加FASN mRNA的稳定性，从而重编程FA代谢并促进GC进展。在这项研究中，通过比较来自配对原发性和腹膜转移肿瘤的lncRNA测序数据以及来自非转移和转移样本的公开转录组数据，我们明确了一个新的lncRNA TENM3-AS1。我们发现TENM3-AS1在转移性和晚期原发肿瘤中异常激活，并与胃癌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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The EGR1-mediated lncRNA TENM3-AS1 potentiates gastric cancer metastasis via reprogramming fatty acid metabolism

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. 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. 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. 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.

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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