E2F1 and MYC activated SNHG15 promotes gastric cancer progression via interacting with miR-24-3p to regulate cell cycle and ferroptosis

Abstract Background: The regulatory loop between long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) plays a dynamic role in transcriptional and translational regulation, and is involved in carcinogenesis. However, the regulatory circuitry between lncRNAs and miRNAs in gastric cancer (GC) remains elusive.Methods: The novel SNHG15 was identifed 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, fuorescence in situ hybridization (FISH), luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay. Meanwhile, the oncogenic activity of SNHG15 was explored in both GC cells and animal xenograft studies.Results: SNHG15 is highly expressed in GC. The enhanced SNHG15 exists in GC and positively correlates 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 enhance its expression. Meanwhile, SNHG15 increased E2F1, MYC and CDC25A mRNA expression by sponging miR-24-3p. In addition, SNHG15 could also inhibit ferroptosis through a miR-24-3p-mediated regulation of MDM2/p53/SLC7A11 signalling axis.Conclusions: Our results support a novel model in which the E2F1, MYC/SNHG15/miR-24-3p crosstalk served as the critical effectors in GC tumorigenesis and progression, providing a new therapeutic direction in the treatment of GC.