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<p>Colorectal cancer (CRC) is still a deadly malignancy all over the world. Previous studies have indicated that exosomes could remodel the microenvironment and promote tumor development. Furthermore, Galectin 3 (also known as LGALS3) was found to be present within the lumen of exosomes and participate in tumor progression. However, the effects of exosomal LGALS3 on CRC progression are still unclear. The advanced CRC cellular heterogeneity was identified in GSM7349819 database using scRNA-Seq analysis. Through the analysis of GSM7349819 database, transcriptome GSE159112 database, and GeneCards database, potential targets of lipid metabolism-related differential expression genes (DEGs) in macrophages and stem cells during CRC progression were identified. LGALS3 and Y-box binding protein 1 (YBX1) expression was determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. M2 polarization of macrophages was determined by measuring the M2-specific cell surface markers and cytokines. Binding between LGALS3 and YBX1 was analyzed using m5C RIP, RIP, and dual-luciferase reporter assays. PMA-treated THP1 cells were exposed to IL-4 and IL-13, generating M2-TAMs (THP1-M2). Effects of M2-TAM-derived exosomal YBX1 and LGALS3 on CRC development were assessed. Cell proliferation, invasion, sphere formation ability, and apoptosis were determined using EdU, Transwell, sphere formation, and flow cytometry. Oil Red O staining was applied for lipid accumulation. Role of M2-TAM-derived exosomal YBX1 on CRC tumor growth was determined in vivo experiments. Public database analysis exhibited that lipid metabolism-related gene LGALS3 was upregulated in CRC stem cells and M2 macrophages. Compared with THP1-M0, LGALS3 was increased in THP1-M2. LGALS3 was transferred from M2 TAMs to CRC cells via exosomes. M2 TAM-derived exosomal LGALS3 knockdown repressed CRC cell proliferation, invasion, stemness, lipid metabolism, promoted apoptosis, and inhibited tumor growth in vivo. Mechanistically, YBX1 recognized m5C modifications in LGALS3 mRNA and maintained mRNA stability in M2 TAM. YBX1-mediated m5C modification of exosomal LGALS3 derived from M2 TAM could promote CRC cell growth and lipid metabolism, providing a highly potential target for CRC.</p>

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YBX1-mediated m5C modification of exosomal LGALS3 derived from M2 tumor-associated macrophages drives colorectal cancer cell malignant behaviors

  • 期刊论文

  • 发表日期：

    2026年8月3日

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  • Lu Yang,
  • Xiaoling Zhang,
  • Tao Meng,
  • Daiyuan Dong,
  • Xiangjie Fang,
  • Sujuan Li,
  • Tingmin Chang

摘要

Colorectal cancer (CRC) is still a deadly malignancy all over the world. Previous studies have indicated that exosomes could remodel the microenvironment and promote tumor development. Furthermore, Galectin 3 (also known as LGALS3) was found to be present within the lumen of exosomes and participate in tumor progression. However, the effects of exosomal LGALS3 on CRC progression are still unclear. The advanced CRC cellular heterogeneity was identified in GSM7349819 database using scRNA-Seq analysis. Through the analysis of GSM7349819 database, transcriptome GSE159112 database, and GeneCards database, potential targets of lipid metabolism-related differential expression genes (DEGs) in macrophages and stem cells during CRC progression were identified. LGALS3 and Y-box binding protein 1 (YBX1) expression was determined using real-time quantitative polymerase chain reaction (RT-qPCR) and western blot. M2 polarization of macrophages was determined by measuring the M2-specific cell surface markers and cytokines. Binding between LGALS3 and YBX1 was analyzed using m5C RIP, RIP, and dual-luciferase reporter assays. PMA-treated THP1 cells were exposed to IL-4 and IL-13, generating M2-TAMs (THP1-M2). Effects of M2-TAM-derived exosomal YBX1 and LGALS3 on CRC development were assessed. Cell proliferation, invasion, sphere formation ability, and apoptosis were determined using EdU, Transwell, sphere formation, and flow cytometry. Oil Red O staining was applied for lipid accumulation. Role of M2-TAM-derived exosomal YBX1 on CRC tumor growth was determined in vivo experiments. Public database analysis exhibited that lipid metabolism-related gene LGALS3 was upregulated in CRC stem cells and M2 macrophages. Compared with THP1-M0, LGALS3 was increased in THP1-M2. LGALS3 was transferred from M2 TAMs to CRC cells via exosomes. M2 TAM-derived exosomal LGALS3 knockdown repressed CRC cell proliferation, invasion, stemness, lipid metabolism, promoted apoptosis, and inhibited tumor growth in vivo. Mechanistically, YBX1 recognized m5C modifications in LGALS3 mRNA and maintained mRNA stability in M2 TAM. YBX1-mediated m5C modification of exosomal LGALS3 derived from M2 TAM could promote CRC cell growth and lipid metabolism, providing a highly potential target for CRC.