通过CCL5/GGT5轴调节癌症肿瘤转移和脂质代谢重编程
Regulation of tumor metastasis and lipid metabolism reprogramming via the CCL5/GGT5 axis in gastric cancer.
摘要(中文译文)
胃癌（GC）是一种高度侵袭性且分子异质性显著的恶性肿瘤。在肿瘤微环境中，癌相关成纤维细胞（CAFs）构成胃癌生态系统中的关键细胞组分，其浸润密度升高与胃癌患者的肿瘤转移能力及疾病进展相关。我们的研究阐明了CAF分泌的趋化因子CCL5通过上调GGT5表达水平促进胃癌转移进展的分子通路。利用TCGA-STAD数据库及GEO数据集（GSE84437），我们检测了胃癌特征性的代谢紊乱。通过分子分型，胃癌标本被分为三个不同的异质性亚型，其中Cluster 2表现出更差的无预后结局和更具侵袭性的临床特征。此外，通路富集分析揭示了与不饱和脂肪酸生物合成及细胞外基质相关代谢过程有关的代谢通路显著激活。通过生物信息学分析，我们鉴定出γ-谷氨酰转移酶5（GGT5），这是调控花生四烯酸代谢的关键酶。GGT5是一种与细胞外基质重塑和细胞迁移相关的酶，在胃癌中呈高表达。细胞因子流式细胞术结果表明，转移性胃癌患者外周血中CCL5的表达高于原位胃癌患者。我们证明，细胞外CAF来源的趋化因子CCL5增加可导致GGT5表达上调、EMT相关标志物表达改变，并促进裸鼠肝转移。总之，靶向CAF来源的趋化因子CCL5介导的GGT5级联通路可能为胃癌提供一种新的治疗策略。
Abstract
Gastric carcinoma (GC) represents a highly invasive and molecularly diverse malignant neoplasm. Within the tumor microenvironment, cancer-associated fibroblasts (CAFs) constitute a critical cellular component of the GC ecosystem, where elevated infiltration densities is correlated with the metastatic ability of the tumor and the progression of the disease in GC patients. Our investigation elucidated the molecular pathway through which CAF-secreted chemokine CCL5 facilitates GC metastatic progression via upregulation of GGT5 expression levels. Utilizing the TCGA-STAD database alongside the GEO dataset (GSE84437), we examined metabolic perturbations characteristic of GC. Through molecular profiling, GC specimens were stratified into three distinct heterogeneous subtypes, wherein Cluster 2 demonstrated inferior prognostic outcomes and more aggressive clinical characteristics. Furthermore, pathway enrichment analyses revealed significant activation of metabolic pathways associated with unsaturated fatty acid biosynthesis and extracellular matrix-related metabolic processes. Through bioinformatics analysis, we identified γ-glutamyltransferase 5 (GGT5), a key enzyme regulating arachidonic acid metabolism. GGT5, an enzyme associated with extracellular matrix remodeling and cell migration, showed high expression in GC. Cytokine flow cytometry results indicated that the expression of CCL5 in the peripheral blood of metastatic GC patients was higher compared to those with gastric carcinoma in situ. We demonstrated that increased extracellular CAF-derived chemokine CCL5 leads to upregulation of GGT5 expression, alterations in EMT-related marker expression, and promotes liver metastasis in nude mice. In conclusion, targeting the CAF-derived chemokine CCL5-mediated GGT5 cascade may provide a novel therapeutic approach for GC.
如何引用
AMA
Jingxin Yin, Yang Chen, Penglei Zhai, Yang Lu, Yi Shi, Liping Su, et al. Regulation of tumor metastasis and lipid metabolism reprogramming via the CCL5/GGT5 axis in gastric cancer.. International journal of biological macromolecules. 2026; doi:10.1016/j.ijbiomac.2026.151812.
APA
Jingxin Yin, Yang Chen, Penglei Zhai, Yang Lu, Yi Shi, Liping Su, et al (2026). Regulation of tumor metastasis and lipid metabolism reprogramming via the CCL5/GGT5 axis in gastric cancer.. International journal of biological macromolecules. https://doi.org/10.1016/j.ijbiomac.2026.151812
GB/T 7714
Jingxin Yin, Yang Chen, Penglei Zhai, Yang Lu, Yi Shi, Liping Su, et al. Regulation of tumor metastasis and lipid metabolism reprogramming via the CCL5/GGT5 axis in gastric cancer.[J]. International journal of biological macromolecules, 2026 doi:10.1016/j.ijbiomac.2026.151812.
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