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Background <p>This study aimed to investigate the role of Collagen triple helix repeat protein 1 (<i>CTHRC1</i>) in Wilms’ tumor (WT) progression and elucidate its molecular mechanism in promoting WT malignancy through regulation of M2-type tumor-associated macrophages (M2-TAMs) infiltration and polarization.</p> Methods <p>Bioinformatics analysis was conducted using public databases to examine CTHRC1 expression and immune cell infiltration in WT. Single-cell sequencing was employed to analyze expression patterns of <i>CTHRC1</i> and M2-TAMs markers. <i>CTHRC1</i> expression and M2-TAM infiltration were validated in WT tissues using RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence. In vitro and in vivo experiments were performed to investigate the biological functions of <i>CTHRC1</i> in WT and its effects on M2-TAMs polarization. Transcriptome sequencing and bioinformatics analysis were used to explore potential signaling pathways. The TNFSF9-TNFRSF9 axis was further investigated through neutralizing antibody rescue experiments and co-localization analysis. The role of M2-TAMs in promoting WT progression via the PI3K/AKt pathway was examined using xenograft models and in vitro experiments.</p> Results <p><i>CTHRC1</i> and M2-TAMs were significantly overexpressed in WT tissues and positively correlated. <i>CTHRC1</i> overexpression promoted WT cell proliferation, inhibited apoptosis, and induced M2-TAMs polarization both in vitro and in vivo. Transcriptome analysis revealed that <i>CTHRC1</i> regulated M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. <i>CTHRC1</i> overexpression upregulated TNFSF9: expression and secretion in tumor cells, promoting its binding to TNFRSF9 on M2-TAMs. Neutralizing <i>TNFSF9</i> or knockdown of <i>TNFRSF9</i> significantly attenuated <i>CTHRC1</i>-induced M2-TAM infiltration and polarization. M2-TAMs promoted WT progression by activating the PI3K/Akt pathway in tumor cells. Inhibition of PI3K/Akt signaling reversed M2-TAM-mediated WT progression.</p> Conclusions <p><i>CTHRC1</i> promotes WT progression by inducing M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. M2-TAMs, in turn, enhance WT malignancy by activating the PI3K/Akt pathway in tumor cells. These findings provide new potential biomarkers and therapeutic targets for WT diagnosis and treatment.</p>

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Mechanistic study of CTHRC1 in promoting Wilms’ tumor progression by regulating M2-type tumor-associated macrophages polarization

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月8日

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  • Yingquan Zhuo,
  • Xiaoyun Feng,
  • Wenqi Zhang,
  • Jun Du,
  • Xu Sun,
  • Xi Luo,
  • Wei Wang,
  • Hua Jiang,
  • Huajian Gu

摘要

Background

This study aimed to investigate the role of Collagen triple helix repeat protein 1 (CTHRC1) in Wilms’ tumor (WT) progression and elucidate its molecular mechanism in promoting WT malignancy through regulation of M2-type tumor-associated macrophages (M2-TAMs) infiltration and polarization.

Methods

Bioinformatics analysis was conducted using public databases to examine CTHRC1 expression and immune cell infiltration in WT. Single-cell sequencing was employed to analyze expression patterns of CTHRC1 and M2-TAMs markers. CTHRC1 expression and M2-TAM infiltration were validated in WT tissues using RT-qPCR, Western blot, immunohistochemistry, and immunofluorescence. In vitro and in vivo experiments were performed to investigate the biological functions of CTHRC1 in WT and its effects on M2-TAMs polarization. Transcriptome sequencing and bioinformatics analysis were used to explore potential signaling pathways. The TNFSF9-TNFRSF9 axis was further investigated through neutralizing antibody rescue experiments and co-localization analysis. The role of M2-TAMs in promoting WT progression via the PI3K/AKt pathway was examined using xenograft models and in vitro experiments.

Results

CTHRC1 and M2-TAMs were significantly overexpressed in WT tissues and positively correlated. CTHRC1 overexpression promoted WT cell proliferation, inhibited apoptosis, and induced M2-TAMs polarization both in vitro and in vivo. Transcriptome analysis revealed that CTHRC1 regulated M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. CTHRC1 overexpression upregulated TNFSF9: expression and secretion in tumor cells, promoting its binding to TNFRSF9 on M2-TAMs. Neutralizing TNFSF9 or knockdown of TNFRSF9 significantly attenuated CTHRC1-induced M2-TAM infiltration and polarization. M2-TAMs promoted WT progression by activating the PI3K/Akt pathway in tumor cells. Inhibition of PI3K/Akt signaling reversed M2-TAM-mediated WT progression.

Conclusions

CTHRC1 promotes WT progression by inducing M2-TAMs polarization through the TNFSF9-TNFRSF9 axis. M2-TAMs, in turn, enhance WT malignancy by activating the PI3K/Akt pathway in tumor cells. These findings provide new potential biomarkers and therapeutic targets for WT diagnosis and treatment.