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<p>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with tumor-associated macrophages (TAMs), predominantly M2-polarized, shaping a tumor-promoting microenvironment. ETS proto-oncogene 2 (ETS2) is aberrantly upregulated in CRC, but its role in exosome-mediated intercellular communication and TAM polarization remains unclear. Here, public datasets and single-cell RNA sequencing were analyzed to characterize ETS2 expression and cellular distribution in CRC. Co-culture of THP-1-derived M0 macrophages with CRC cells (LoVo and HCT-116), combined with isolation of tumor-derived exosomes, was used to assess exosome-mediated ETS2 transfer and macrophage M2 polarization. CRC cell proliferation, migration, apoptosis, CD8⁺ T cell apoptosis, and macrophage M2 polarization were evaluated by CCK-8, EdU incorporation, flow cytometry, RT-qPCR, and Transwell assays. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed transcriptional activation of pre-mRNA processing factor 4 (PRPF4) by ETS2, and a xenograft mouse model was used to assess in vivo effects. ETS2 expression was elevated in CRC tissues and TAMs and correlated positively with M2 polarization. Silencing ETS2 inhibited CRC cell proliferation and migration, promoted apoptosis, reduced macrophage M2 polarization, and decreased CD8⁺ T cell apoptosis. Mechanistically, ETS2 activated PRPF4 transcription, and PRPF4 overexpression reversed the inhibitory effects of ETS2 knockdown. CRC-derived exosomes mediated ETS2 transfer to macrophages, promoting M2 polarization, and in vivo PRPF4 overexpression significantly rescued tumor growth suppressed by ETS2 knockdown. These findings indicate that exosomal ETS2 promotes CRC progression and M2 macrophage polarization via PRPF4, highlighting the ETS2/PRPF4 axis as a potential therapeutic target.</p>

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Colorectal cancer-derived exosomal ETS2 promotes macrophage M2 polarization by transcriptionally activating PRPF4

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Dengfeng Hou,
  • Zhongyuan Bai,
  • Jiaxin Zhao,
  • Haipeng Fan,
  • Junsheng Chen,
  • Wenqi Bai

摘要

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with tumor-associated macrophages (TAMs), predominantly M2-polarized, shaping a tumor-promoting microenvironment. ETS proto-oncogene 2 (ETS2) is aberrantly upregulated in CRC, but its role in exosome-mediated intercellular communication and TAM polarization remains unclear. Here, public datasets and single-cell RNA sequencing were analyzed to characterize ETS2 expression and cellular distribution in CRC. Co-culture of THP-1-derived M0 macrophages with CRC cells (LoVo and HCT-116), combined with isolation of tumor-derived exosomes, was used to assess exosome-mediated ETS2 transfer and macrophage M2 polarization. CRC cell proliferation, migration, apoptosis, CD8⁺ T cell apoptosis, and macrophage M2 polarization were evaluated by CCK-8, EdU incorporation, flow cytometry, RT-qPCR, and Transwell assays. Chromatin immunoprecipitation and dual-luciferase reporter assays confirmed transcriptional activation of pre-mRNA processing factor 4 (PRPF4) by ETS2, and a xenograft mouse model was used to assess in vivo effects. ETS2 expression was elevated in CRC tissues and TAMs and correlated positively with M2 polarization. Silencing ETS2 inhibited CRC cell proliferation and migration, promoted apoptosis, reduced macrophage M2 polarization, and decreased CD8⁺ T cell apoptosis. Mechanistically, ETS2 activated PRPF4 transcription, and PRPF4 overexpression reversed the inhibitory effects of ETS2 knockdown. CRC-derived exosomes mediated ETS2 transfer to macrophages, promoting M2 polarization, and in vivo PRPF4 overexpression significantly rescued tumor growth suppressed by ETS2 knockdown. These findings indicate that exosomal ETS2 promotes CRC progression and M2 macrophage polarization via PRPF4, highlighting the ETS2/PRPF4 axis as a potential therapeutic target.