SLC38A7 promotes gastric cancer progression through activating Wnt/β-catenin signaling via interaction with MYH9.
SLC38A7通过与MYH9相互作用激活Wnt/β-catenin信号通路，从而促进胃癌进展。
Kai Li, Shuyang Sun, Yunhe Gao, Yixun Lu, Xinxin Xu, Lin Chen, Zhi Qiao, Zhanyu Yang (2026) SLC38A7 promotes gastric cancer progression through activating Wnt/β-catenin signaling via interaction with MYH9. Chin Med J (Engl) (IF: 7.3) 2 区
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Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide. Solute carrier family 38 member 7 (SLC38A7), a lysosome-localized glutamine transporter, has been implicated in poor cancer prognosis and chemoresistance, but its biological role in GC is not well understood. This study aimed to investigate the biological function of SLC38A7 in GC progression and to elucidate the underlying signaling mechanism.The expression pattern and clinical relevance of SLC38A7 were analyzed using public datasets from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project, and validated in 60 paired GC tissues collected at the Chinese People's Liberation Army (PLA) General Hospital. Gain- and loss-of-function experiments were conducted in MKN-28 and MGC-803 to evaluate the effects of SLC38A7 on cell proliferation, migration, and invasion under glutamine-replete and glutamine-deprived conditions. Protein-protein interactions were assessed by co-immunoprecipitation and mass spectrometry. Site-directed mutagenesis was performed to identify key residues mediating SLC38A7 function. Downstream signaling was analyzed by western blotting and ubiquitination assays. A xenograft mouse model was established to determine the role of SLC38A7 in tumor growth in vivo.SLC38A7 expression was significantly upregulated in GC tissues and cell lines and was associated with poor patient prognosis. Functional assays demonstrated that SLC38A7 promoted GC cell proliferation, migration, and invasion, particularly under glutamine-deprived conditions. Mechanistically, SLC38A7 interacted with myosin heavy chain 9 (MYH9), facilitating glycogen synthase kinase-3β (GSK-3β) ubiquitination and degradation, which led to activation of the wingless/int-1 (Wnt)/β-catenin signaling pathway. Mutation of key SLC38A7 residues (E12 and Q3) disrupted its interaction with MYH9 and attenuated downstream signaling. Pharmacological inhibition of GSK-3β partially rescued the effects of SLC38A7 silencing in vitro. In vivo, SLC38A7 knockdown significantly suppressed tumor growth.SLC38A7 promotes gastric cancer progression by activating the Wnt/β-catenin signaling pathway through MYH9-dependent regulation of GSK-3β ubiquitination.Copyright © 2026 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.
胃癌（GC）仍然是全球癌症相关死亡的主要原因之一。溶酶体定位的谷氨酰胺转运蛋白——溶质载体家族38成员7（SLC38A7）与胃癌预后不良和化疗耐药密切相关，但其在胃癌中的生物学作用尚不明确。本研究旨在探讨SLC38A7在胃癌进展中的生物学功能，并阐明其潜在的信号通路机制。我们利用癌症基因组图谱（TCGA）和基因型-组织表达（GTEx）项目的公共数据集分析了SLC38A7的表达模式及其临床意义，并在中国人民解放军总医院收集的60例配对胃癌组织样本中进行了验证。在MKN-28和MGC-803细胞中进行了功能获得和功能缺失实验，以评估SLC38A7在谷氨酰胺充足和缺乏条件下对细胞增殖、迁移和侵袭的影响。采用免疫共沉淀和质谱分析评估了蛋白质-蛋白质相互作用。通过定点诱变鉴定了介导SLC38A7功能的关键残基。采用蛋白质印迹和泛素化分析研究了下游信号通路。建立了异种移植小鼠模型，以确定SLC38A7在体内肿瘤生长中的作用。SLC38A7在胃癌组织和细胞系中表达显著上调，且与患者预后不良相关。功能实验表明，SLC38A7促进胃癌细胞的增殖、迁移和侵袭，尤其是在谷氨酰胺缺乏条件下。从机制上讲，SLC38A7 与肌球蛋白重链 9 (MYH9) 相互作用，促进糖原合成酶激酶-3β (GSK-3β) 的泛素化和降解，进而激活 Wnt/β-catenin 信号通路。SLC38A7 关键残基（E12 和 Q3）的突变破坏了其与 MYH9 的相互作用，并减弱了下游信号传导。体外实验表明，GSK-3β 的药理学抑制可部分逆转 SLC38A7 沉默的影响。体内实验表明，SLC38A7 敲低显著抑制了肿瘤生长。SLC38A7 通过 MYH9 依赖性调控 GSK-3β 泛素化，激活 Wnt/β-catenin 信号通路，从而促进胃癌进展。版权所有 © 2026 中华医学会，由 Wolters Kluwer, Inc. 根据 CC-BY-NC-ND 许可协议制作。
Links
http://www.ncbi.nlm.nih.gov/pubmed/41980890http://dx.doi.org/10.1097/CM9.0000000000004090
