FAM83A通过调控GSK3β/β-Catenin信号轴参与肺腺癌的发展

FAM83A Promotes Lung Adenocarcinoma Progression by Modulating the GSK3β/β-Catenin Signaling Axis

摘要: 背景：肺腺癌(LUAD)仍然是导致癌症死亡的主要原因之一。FAM83A作为FAM83家族的一员，已被证明参与了致癌信号的传导，但其在LUAD中的机制作用尚不完全明了。我们假设FAM83A通过调控GSK3β/β-catenin轴在LUAD中发挥作用。方法：我们分析了来自TCGA-LUAD的公共RNA-seq数据和临床数据，以评估FAM83A的表达、其与总生存期的关联以及通路富集情况。在LUAD细胞系中，通过瞬时过表达或siRNA敲低来干扰FAM83A的表达。分子检测包括qPCR和Western Blot分析，检测FAM83A、GSK3β (总蛋白/磷酸化形式)、β-catenin及下游靶标(如Cyclin D1)的表达水平。此外，通过使用GSK3β的药理学抑制剂(氯化锂)来探讨通路依赖性。同时，NC组细胞处理INH抑制剂，以验证siRNA敲低与INH抑制剂处理组的结果是否一致。结果：在LUAD中，FAM83A显著上调，并且高表达的FAM83A与较差的总生存期相关。基因集富集分析支持β-catenin相关通路的激活。体外实验中，FAM83A过表达促进了β-catenin和Cyclin D1的水平升高，并伴随GSK3β抑制性磷酸化的增加；相反，FAM83A敲低则降低了这些标志物的水平。在NC组细胞中使用INH抑制剂处理后，观察到与FAM83A敲低组相似的效应，验证了这两种处理方法在调控β-catenin信号方面的一致性。结果表明，FAM83A至少部分通过GSK3β调控β-catenin的活性。结论：FAM83A在LUAD中上调，并通过调控GSK3β/β-catenin信号轴发挥机制作用。整合生物信息学分析与分子验证结果提示FAM83A是一个通路水平的调节因子，并可能作为LUAD的潜在生物标志物。这些发现为未来的转化研究提供了简明的机制框架。

Abstract: Background: Lung adenocarcinoma (LUAD) remains a major contributor to cancer-related mortality worldwide. FAM83A, a member of the FAM83 protein family, has been implicated in oncogenic signaling; however, its functional mechanism in LUAD has not been fully elucidated. We hypothesized that FAM83A promotes LUAD progression by modulating the GSK3β/β-catenin signaling axis. Methods: RNA-seq and clinical data from the TCGA-LUAD cohort were analyzed to assess FAM83A expression, its association with overall survival, and enriched signaling pathways. In LUAD cell lines, transient overexpression or siRNA-mediated knockdown of FAM83A was performed. qPCR and Western blot analyses were used to evaluate the expression of FAM83A, GSK3β (total and phosphorylated forms), β-catenin, and downstream effectors such as Cyclin D1. Lithium chloride was employed as a pharmacological inhibitor of GSK3β to examine pathway dependency. Furthermore, negative control cells were treated with INH inhibitors to confirm whether their effects aligned with those induced by siRNA-mediated knockdown. Results: FAM83A was significantly upregulated in LUAD and its high expression correlated with reduced overall survival. Gene set enrichment analysis supported activation of β-catenin-related signaling pathways. In vitro, FAM83A overexpression increased β-catenin and Cyclin D1 expression and elevated inhibitory phosphorylation of GSK3β, while FAM83A knockdown had the opposite effect. Treatment of control cells with INH inhibitors yielded similar phenotypes to FAM83A knockdown, validating the consistency of both approaches in suppressing β-catenin signaling. These findings suggest that FAM83A enhances β-catenin activity at least in part through regulation of GSK3β. Conclusion: FAM83A is upregulated in LUAD and promotes tumor progression by modulating the GSK3β/β-catenin signaling axis. Integrating bioinformatic analysis with molecular validation, this study identifies FAM83A as a pathway-level regulatory factor and a promising biomarker for LUAD. These findings provide a mechanistic rationale for future translational investigations.