Background: Epithelial–mesenchymal transition (EMT) is a fundamental process that drives invasion and metastasis in patients with diffuse-type gastric cancer (DGC). The role of SMARCD3, a subunit of the SWI/SNF chromatin remodeling complex, in this process is largely unknown. The aim of this study is to elucidate the molecular mechanism through which SMARCD3 integrates with the PI3K-AKT and WNT/β-catenin signaling pathways to promote EMT and gastric cancer progression.Methods: Stable SMARCD3-overexpressing MKN45 and MKN74 cell lines were established. RNA sequencing (RNA-seq) was performed to investigate signaling alterations. Western blot analysis confirmed the expression of EMT markers (Snail and Slug) and the phosphorylation of AKT (Ser473) and GSK3β (Ser9). PI3K dependency was tested using the inhibitor LY294002. Cooperative effects were examined by activating the WNT pathway with WNT3A.Results: SMARCD3 overexpression upregulated PI3K-AKT and WNT signaling, which correlated with increased Snail/Slug expression and increased AKT/GSK3β phosphorylation. GSK3β inactivation (pSer9) stabilizes Snail, driving EMT. LY294002 treatment suppressed Snail/Slug expression, attenuated AKT activation, and reversed the mesenchymal phenotype. Furthermore, WNT3A treatment synergistically increased nuclear Snail accumulation.Conclusions: SMARCD3 acts as a critical epigenetic regulator that promotes EMT in patients with gastric cancer through the integration of the PI3K-AKT and WNT/β-catenin pathways. Targeting this SMARCD3-mediated mechanism offers a promising therapeutic strategy to inhibit metastasis and improve outcomes for patients with gastric cancer.
背景：上皮-间质转化（EMT）是驱动弥漫型胃癌（DGC）患者侵袭和转移的关键过程。SMARCD3作为SWI/SNF染色质重塑复合物的亚基，在此过程中的作用尚不明确。本研究旨在阐明SMARCD3如何通过整合PI3K-AKT与WNT/β-catenin信号通路促进EMT及胃癌进展的分子机制。 方法：建立稳定过表达SMARCD3的MKN45和MKN74细胞系。通过RNA测序（RNA-seq）分析信号通路变化，蛋白质印迹法检测EMT标志物（Snail和Slug）表达及AKT（Ser473）与GSK3β（Ser9）磷酸化水平。使用抑制剂LY294002验证PI3K依赖性，并通过WNT3A激活WNT通路探究协同效应。 结果：SMARCD3过表达上调PI3K-AKT与WNT信号通路，伴随Snail/Slug表达升高及AKT/GSK3β磷酸化增强。GSK3β失活（pSer9）可稳定Snail蛋白，驱动EMT进程。LY294002处理能抑制Snail/Slug表达、减弱AKT活化并逆转间质表型。此外，WNT3A处理可协同增加核内Snail蛋白累积。 结论：SMARCD3作为关键表观遗传调控因子，通过整合PI3K-AKT与WNT/β-catenin信号通路促进胃癌EMT进程。靶向该SMARCD3介导的调控机制，为抑制胃癌转移、改善患者预后提供了潜在治疗策略。
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