SNHG15‐mediated feedback loop interplays with HNRNPA1/SLC7A11/GPX4 pathway to promote gastric cancer progression

• Published in: Cancer science 2024-07, Vol.115 (7), p.2269-2285
• Main Authors: Duan, Yantao, Yan, Yonghao, Fu, Hongbing, Dong, Yang, Li, Kun, Ye, Zaisheng, Dou, Yi, Huang, Binhao, Kang, Wei, Wei, Gong‐Hong, Cai, Qiliang, Xu, Dazhi, Zhou, Donglei
• Format: Article
• Language: English
• Subjects: Amino Acid Transport System y+ - genetics; Amino Acid Transport System y+ - metabolism; Animals; Cell growth; Cell Line, Tumor; Cell migration; Cell Movement - genetics; Cell Proliferation - genetics; Cytoplasm; Disease Progression; E2F1; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Feedback, Physiological; Female; Ferroptosis; Ferroptosis - genetics; Gastric cancer; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genomes; Heterogeneous Nuclear Ribonucleoprotein A1 - genetics; Heterogeneous Nuclear Ribonucleoprotein A1 - metabolism; HNRNPA1; Humans; Male; Medical prognosis; Metastasis; Mice; Mice, Nude; MicroRNAs; Middle Aged; Molecular modelling; MYC; Myc protein; Non-coding RNA; Original; Patients; Phospholipid Hydroperoxide Glutathione Peroxidase - genetics; Phospholipid Hydroperoxide Glutathione Peroxidase - metabolism; Prognosis; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Signal Transduction - genetics; SNHG15; Stomach Neoplasms - genetics; Stomach Neoplasms - metabolism; Stomach Neoplasms - pathology; Survival analysis; Transcription factors; Tumorigenesis
• ISSN: 1347-9032; 1349-7006; 1349-7006
• DOI: 10.1111/cas.16181

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. SNHG15 can be transcriptionally activated by E2F1 and MYC. Subsequently, SNHG15 forms a molecular decoy for miR‐24‐3p, a miRNA targeting E2F1 and MYC for degradation, thereby contributing to increased expression of E2F1 and MYC. SNHG15 also enhances the stability of SLC7A11 in the cytoplasm by binding HNRNPA1, and inhibits ferroptosis through an HNRNPA1‐dependent regulation of the SLC7A11/GPX4 axis.