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Background <p>Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with lymphatic metastasis serving as a major route of dissemination and a key determinant of poor prognosis. Tumour-associated lymphangiogenesis (TALA), driven primarily by VEGFC and its receptor VEGFR3, promotes the formation of new lymphatic vessels, facilitating the dissemination of tumour cells to regional lymph nodes and distant sites. This study aimed to investigate the prognostic impact of TALA in CRC and elucidate its underlying molecular mechanisms.</p> Methods <p>Using the TCGA-COADREAD cohort, consensus clustering was performed based on canonical TALA-related genes to define the TALA-High and TALA-Low subtypes. A TALA prognostic score (TALAPS) model incorporating SYPL2, LRRC4C, and FAM43B was developed using weighted gene co-expression network analysis (WGCNA), differential expression analysis, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression. Functional validation was performed in HCT116 cells through shRNA-mediated knockdown and gene overexpression.</p> Results <p>The TALA-High subtype exhibited significant activation of lymphatic vessel regulatory pathways, accompanied by elevated expression of key molecules. The TALAPS model demonstrated time-dependent AUC values &gt; 0.60 in the training, validation, entire cohorts, and external GEO cohort. The high-TALAPS group exhibited significantly poorer overall survival and was strongly positively correlated with TALA biomarkers. In vitro experiments confirmed that knockdown of SYPL2, LRRC4C, or FAM43B markedly suppressed cell viability, migration, invasion, and activation of the p-AKT/p-ERK/HIF1α/VEGFC/LYVE1 axis, whereas overexpression significantly enhanced these phenotypes. Dysregulation of these three genes suggests their potential association with tumor lymphatic metastasis.</p> Conclusion <p>As a TALA-specific three-gene prognostic model, TALAPS serves as a reliable biomarker for prognostic risk stratification in patients with CRC. The synergistic effects of SYPL2, LRRC4C, and FAM43B promote dysregulation of the colorectal cancer tumour microenvironment, thereby significantly increasing prognostic risk.</p>

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SYPL2, LRRC4C, and FAM43B define a tumor-associated lymphangiogenesis-related signature with prognostic potential in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Mulati Tuerxun,
  • Xiaohui Wang,
  • Yiliyaer Yilihamu,
  • Mengke Xu,
  • Fujiang Zhang

摘要

Background

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with lymphatic metastasis serving as a major route of dissemination and a key determinant of poor prognosis. Tumour-associated lymphangiogenesis (TALA), driven primarily by VEGFC and its receptor VEGFR3, promotes the formation of new lymphatic vessels, facilitating the dissemination of tumour cells to regional lymph nodes and distant sites. This study aimed to investigate the prognostic impact of TALA in CRC and elucidate its underlying molecular mechanisms.

Methods

Using the TCGA-COADREAD cohort, consensus clustering was performed based on canonical TALA-related genes to define the TALA-High and TALA-Low subtypes. A TALA prognostic score (TALAPS) model incorporating SYPL2, LRRC4C, and FAM43B was developed using weighted gene co-expression network analysis (WGCNA), differential expression analysis, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression. Functional validation was performed in HCT116 cells through shRNA-mediated knockdown and gene overexpression.

Results

The TALA-High subtype exhibited significant activation of lymphatic vessel regulatory pathways, accompanied by elevated expression of key molecules. The TALAPS model demonstrated time-dependent AUC values > 0.60 in the training, validation, entire cohorts, and external GEO cohort. The high-TALAPS group exhibited significantly poorer overall survival and was strongly positively correlated with TALA biomarkers. In vitro experiments confirmed that knockdown of SYPL2, LRRC4C, or FAM43B markedly suppressed cell viability, migration, invasion, and activation of the p-AKT/p-ERK/HIF1α/VEGFC/LYVE1 axis, whereas overexpression significantly enhanced these phenotypes. Dysregulation of these three genes suggests their potential association with tumor lymphatic metastasis.

Conclusion

As a TALA-specific three-gene prognostic model, TALAPS serves as a reliable biomarker for prognostic risk stratification in patients with CRC. The synergistic effects of SYPL2, LRRC4C, and FAM43B promote dysregulation of the colorectal cancer tumour microenvironment, thereby significantly increasing prognostic risk.