Noxa inhibits oncogenesis through ZNF519 in gastric cancer and is suppressed by hsa-miR-200b-3p.

While Phorbol-12-myristate-13-acetate-induced protein 1 (Noxa/PMAIP1) assumes a pivotal role in numerous tumors, its clinical implications and underlying mechanisms of gastric cancer (GC) are yet enigmatic. In this investigation, our primary objective was to scrutinize the clinical relevance and potential mechanisms of Noxa in gastric cancer. Immunohistochemical analysis was conducted on tissue microarrays comprising samples from a meticulously characterized cohort of 84 gastric cancer patients, accompanied by follow-up data, to assess the expression of Noxa. Additionally, Noxa expression levels in gastric cancer clinical samples and cell lines were measured through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. The effect of Noxa expression on the prognosis of patients with gastric cancer was evaluated using Kaplan-Meier survival. Further insight into the role of Noxa in driving gastric cancer progression was gained through an array of experimental techniques, including cell viability assays (CCK8), plate cloning assays, transwell assays, scratch assays, and real-time cell analysis (RTCA). Potential upstream microRNAs (miRNAs) that might modulate Noxa were identified through rigorous bioinformatics analysis, substantiated by luciferase reporter assays and Western blot experiments. Additionally, we utilized RNA sequencing, qRT-PCR, and Western blot to identify proteins binding to Noxa and potential downstream target. Finally, we utilized BALB/c nude mice to explore the role of Noxa in vivo. Our investigation unveiled a marked downregulation of Noxa expression in gastric cancer and underscored its significance as a pivotal prognostic factor influencing overall survival (OS). Noxa overexpression exerted a substantial inhibitory effect on the proliferation, migration and invasion of GC cells. Bioinformatic analysis and dual luciferase reporter assays unveiled the capacity of hsa-miR-200b-3p to interact with the 3'-UTR of Noxa mRNA, thereby orchestrating a downregulation of Noxa expression in vitro, consequently promoting tumor progression in GC. Our transcriptome analysis, coupled with mechanistic validation, elucidated a role for Noxa in modulating the expression of ZNF519 in the Mitophagy-animal pathway. The depletion of ZNF519 effectively reversed the oncogenic attributes induced by Noxa. Upregulation of Noxa expression suppressed the tumorigenesis of GC in vivo. The current investigation sheds light on the pivotal role of the hsa-miR-200b-3p/Noxa/ZNF519 axis in elucidating the pathogenesis of gastric cancer, offering a promising avenue for targeted therapeutic interventions in the management of this challenging malignancy.

EIF4A3 induced circABCA5 promotes the gastric cancer progression by SPI1 mediated IL6/JAK2/STAT3 signaling.

Gastric cancer is one of the most common malignancies of the digestive system with high mortality rates. Recent studies have demonstrated that circRNAs are novel noncoding RNAs that play vital roles in the tumorigenesis and development of gastric cancer. Our study found a novel circRNA, namely, hsa_circ_0107595 (also called circABCA5), that is overexpressed in gastric cancer based on circRNA sequencing. qPCR demonstrated its overexpression in gastric cancer specimens. The overexpression or knockdown of circABCA5 in gastric cancer cell lines was achieved by lentiviral-mediated transfection. All MTS, EdU, Transwell and migration assays and xenograft experiments demonstrated that circABCA5 could promote gastric cancer proliferation, invasion, and migration in vitro and in vivo. Mechanistically, both RIP and RNA pulldown assays confirmed that circABCA5 could bind to the SPI1 protein, upregulate SPI1 expression, and promote its nuclear translocation. SPI1 could further promote the malignant phenotype of gastric cancer by activating IL6/JAK2/STAT3 signaling. In addition, EIF4A3 could directly bind to circABCA5, promoting its stability and expression. Our study reveals that circABCA5 plays a vital role in the diagnosis and prognosis of gastric cancer and may even be developed as a molecular target for the treatment of gastric cancer.