Noxa inhibits oncogenesis through ZNF519 in gastric cancer and is suppressed by hsa-miR-200b-3p
Background: While Phorbol-12-myristate-13-acetate-induced protein 1 (Noxa/PMAIP1)assumes a pivotal role in numerous tumors, its clinical implications and underlying mechanisms ofgastric cancer (GC) are yet enigmatic. In this investigation, our primary objective was to scrutinizethe clinical relevance and potential mechanisms of Noxa in gastric cancer. Methods:Immunohistochemical analysis was conducted on tissue microarrays comprising samples from ameticulously characterized cohort of 84 gastric cancer patients, accompanied by follow-up data, toassess the expression of Noxa. Additionally, Noxa expression levels in gastric cancer clinicalsamples 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 patientswith gastric cancer was evaluated using Kaplan-Meier survival. Further insight into the role of Noxain driving gastric cancer progression was gained through an array of experimental techniques,including cell viability assays (CCK8), plate cloning assays, transwell assays, scratch assays, andreal-time cell analysis (RTCA). Potential upstream microRNAs (miRNAs) that might modulate Noxawere identified through rigorous bioinformatics analysis, substantiated by luciferase reporter assaysand Western blot experiments. Additionally, we utilized RNA sequencing, qRT-PCR, and Westernblot to identify proteins binding to Noxa and potential downstream target. Finally, we utilizedBALB/c nude mice to explore the role of Noxa in vivo. Results: Our investigation unveiled a markeddownregulation of Noxa expression in gastric cancer and underscored its significance as a pivotalprognostic factor influencing overall survival (OS). Noxa overexpression exerted a substantialinhibitory effect on the proliferation, migration and invasion of GC cells. Bioinformatic analysis anddual luciferase reporter assays unveiled the capacity of hsa-miR-200b-3p to interact with the 3'-UTRof Noxa mRNA, thereby orchestrating a downregulation of Noxa expression in vitro, consequentlypromoting 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-animalpathway. The depletion of ZNF519 effectively reversed the oncogenic attributes induced by Noxa.Upregulation of Noxa expression suppressed the tumorigenesis of GC in vivo. Conclusion: Thecurrent investigation sheds light on the pivotal role of the hsa-miR-200b-3p/Noxa/ZNF519 axis inelucidating the pathogenesis of gastric cancer, offering a promising avenue for targeted therapeuticinterventions in the management of this challenging malignancy.