Abstract
Background: Long noncoding RNA (lncRNA) hox transcript antisense intergenic RNA (HOTAIR) is implicated in the progression of gastric cancer (GC) by promoting the microRNA-217 (miR-217)-glypican-5 (GPC5) axis. Quercetin (QCT), a well-known flavonoid, has demonstrated anticancer effects against various malignancies, including GC. However, the impact of QCT on HOTAIR expression and its downstream mediators remains unclear. Objectives: This study aimed to elucidate the antitumor mechanisms of QCT and its regulatory effects on the HOTAIR/miR-217/GPC5 axis in AGS and MKN-45 GC cell lines. Methods: Cellular viability, apoptosis, cell cycle progression, invasion, and oxidative stress markers were assessed using the MTT assay, annexin V-FITC/PI staining, real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and spectrophotometry. Expression levels of HOTAIR, miR-217, and GPC5 were quantified. Results: The QCT significantly downregulated HOTAIR and GPC5 while upregulating miR-217 in both cell lines (P < 0.001). The QCT induced dose-dependent apoptosis and cell cycle arrest, and reduced invasion through upregulation of TP53/PTEN (P < 0.05). Oxidative stress modulation displayed lineage-specific differences, with a marked reduction in malondialdehyde (MDA) in MKN-45 cells (P = 0.013). AGS cells exhibited greater sensitivity to QCT than MKN-45 cells. Conclusions: These findings highlight QCT's ability to inhibit GC progression via the HOTAIR/miR-217/GPC5 axis, with molecular heterogeneity influencing therapeutic response. The QCT emerges as a promising candidate for further investigation as a multifaceted agent against GC, though validation in preclinical models is necessary.