l-谷氨酰胺和SLC3A2在结直肠癌肝转移中的作用

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-06-20 DOI:10.1016/j.intimp.2025.115115

Yang Li , Feng Mo , Hua Mu , Jie Zhi , Zhifei Xin , Wujie Zhao , Qingxia Li , Yitao Jia

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引用次数: 0

摘要

结直肠癌（CRC）肝转移涉及肿瘤细胞与微环境之间复杂的相互作用，但其机制尚不清楚。本研究发现巨噬细胞来源的l-谷氨酰胺是肝转移中驱动巨噬细胞和结直肠癌细胞之间通讯的关键代谢物。巨噬细胞产生l-谷氨酰胺，CRC细胞通过SLC3A2的代谢调节作用感知l-谷氨酰胺。这种感知过程影响了与细胞粘附相关的基因的激活，包括由转录因子FOXA2调节的增强子驱动基因。在转移性结直肠癌细胞中敲除SLC3A2降低FOXA2表达，损害细胞增殖和对肝细胞的粘附。在这些细胞中过表达FOXA2部分恢复了它们的增殖和粘附能力。这些发现表明巨噬细胞来源的l-谷氨酰胺通过slc3a2介导的代谢感知调节FOXA2活性，从而促进结直肠癌细胞的增殖和粘附。本研究揭示了结直肠癌肝转移中代谢物介导的通讯和表观遗传调控的新机制，提供了潜在的治疗靶点。

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Metabolic communication in colorectal cancer liver metastasis: The role of l-glutamine and SLC3A2

Colorectal cancer (CRC) liver metastasis involves complex interactions between tumor cells and the microenvironment, but the mechanisms remain unclear. This study identified macrophage-derived l-glutamine as a key metabolite driving communication between macrophages and CRC cells in liver metastases. Macrophages produced l-glutamine, which CRC cells sensed through the metabolic regulatory role of SLC3A2. This sensing process influenced the activation of genes linked to cell adhesion, including enhancer-driven genes regulated by the transcription factor FOXA2. Knocked down SLC3A2 in metastatic CRC cells reduced FOXA2 expression, impairing cell proliferation and adhesion to hepatocytes. Overexpressed FOXA2 in these cells partially restored their proliferation and adhesion abilities. These findings highlight that macrophage-derived l-glutamine promoted CRC cell proliferation and adhesion by regulating FOXA2 activity through SLC3A2-mediated metabolic sensing. This study has uncovered a novel mechanism of metabolite-mediated communication and epigenetic regulation in CRC liver metastases, providing potential therapeutic targets.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.