A feedback loop comprising E2F1, MYC and SNHG15 interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression

作者：Yantao Duan, Kun Li, Yi Dou, Hongbing Fu, Yang Dong, Yu Wang, Binhao Huang, Wei Kang, Gong‐Hong Wei, Qiliang Cai, Dazhi Xu · 发表于：Research Square · 年份：2023 · DOI：10.21203/rs.3.rs-2565339/v1 · 研究领域：Cancer-related molecular mechanisms research、RNA modifications and cancer、Cholangiocarcinoma and Gallbladder Cancer Studies

Abstract Background: Dysregulation of long non-coding RNAs (lncRNAs) expression plays pivotal roles 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 progression. Methods: 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. The regulatory mechanisms of SNHG15 were investigated by bioinformatics, RNA FISH, luciferase reporter assay, chromatin immunoprecipitation (ChIP), RNA pull-down, RIP-qPCR and luciferase assays. Results: 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 for affecting 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 enhanced 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 cytoplasm by competitively bind...