PDF(Pubmed)
Abstract：
Dysregulation of long noncoding RNA (lncRNA) expression plays a pivotal role in the initiation and progression of gastric cancer (GC). However, the regulation of lncRNA SNHG15 in GC has not been well studied. Mechanisms for ferroptosis by SNHG15 have not been revealed. Here, we aimed to explore SNHG15-mediated biological functions and underlying molecular mechanisms in GC. The novel SNHG15 was identified by analyzing RNA-sequencing (RNA-seq) data of GC tissues from our cohort and TCGA dataset, and further validated by qRT-PCR in GC cells and tissues. Gain- and loss-of-function assays were performed to examine the role of SNHG15 on GC both in vitro and in vivo. SNHG15 was highly expressed in GC. The enhanced SNHG15 was positively correlated with malignant stage and poor prognosis in GC patients. Gain- and loss-of-function studies showed that SNHG15 was required to affect GC cell growth, migration and invasion both in vitro and in vivo. Mechanistically, the oncogenic transcription factors E2F1 and MYC could bind to the SNHG15 promoter and enhance its expression. Meanwhile, SNHG15 increased E2F1 and MYC mRNA expression by sponging miR-24-3p. Notably, SNHG15 could also enhance the stability of SLC7A11 in the cytoplasm by competitively binding HNRNPA1. In addition, SNHG15 inhibited ferroptosis through an HNRNPA1-dependent regulation of SLC7A11/GPX4 axis. Our results support a novel model in which E2F1- and MYC-activated SNHG15 regulates ferroptosis via an HNRNPA1-dependent modulation of the SLC7A11/GPX4 axis, which serves as the critical effectors in GC progression, and provides a new therapeutic direction in the treatment of GC.
摘要：
长链非编码RNA（lncRNA）表达的失调在胃癌（GC）的发生和发展中起着关键作用。然而,lncRNASNHG15在GC中的调控还没有得到很好的研究。SNHG15铁死亡的机制尚未揭示。这里,我们旨在探讨SNHG15介导的GC生物学功能和潜在的分子机制。通过分析来自我们队列和TCGA数据集的GC组织的RNA测序（RNA-seq）数据，鉴定了新的SNHG15。并通过qRT-PCR在GC细胞和组织中进一步验证。进行功能增益和功能丧失测定以检查SNHG15在体外和体内对GC的作用。SNHG15在GC中高度表达。增强的SNHG15与GC患者的恶性分期和不良预后呈正相关。功能增益和丧失研究表明，SNHG15是影响GC细胞生长所必需的，在体外和体内迁移和侵袭。机械上,致癌转录因子E2F1和MYC可以与SNHG15启动子结合并增强其表达。同时,SNHG15通过增强miR-24-3p增加E2F1和MYCmRNA表达。值得注意的是,SNHG15还可以通过竞争性结合HNRNPA1来增强SLC7A11在细胞质中的稳定性。此外,SNHG15通过SLC7A11/GPX4轴的HNRNPA1依赖性调节抑制铁凋亡。我们的结果支持了一个新的模型，其中E2F1-和MYC激活的SNHG15通过SLC7A11/GPX4轴的HNRNPA1依赖性调节铁凋亡，作为GC进展的关键效应，为GC的治疗提供了新的治疗方向。
