SCIENCE@home

Crosstalk between the wnt signaling pathway and axon guidance molecules reveals a novel signature for accurately predicting diagnosis, prognosis, and immune landscape in colorectal cancer.

Wenyi Zhao,Tiegang Li,Jinbao Zong,Fang Zhang,Min-wei Zhou,Yufang Hou,Zheng Yan,Silin Lv,Zifan Zeng,Liu Yang,Yuexia Che,X. Ren,Yixin Zhou,Zengni Zhu,Min Yang

Published 2025 in International Journal of Surgery

ABSTRACT

BACKGROUND Despite the Wnt signaling pathway and axon guidance molecules are critical players in the malignant progression of colorectal cancer (CRC), their specific implications in CRC remain uncertain. This study aimed to construct a novel gene signature related to Wnt signaling and axon guidance (WARGsSig) to predict diagnosis, prognosis, and immune microenvironment in patients with CRC. MATERIALS AND METHODS Utilizing RNA-sequencing data from a liver metastasis model of CRC in C57BL/6 J mice, along with RNA sequencing data from various CRC cohorts, a novel WARGsSig model was developed and validated. These signatures were evaluated for its associations with diagnosis, prognosis, clinical features, biological pathways, and immune landscape, using multiple machine learning algorithms and diverse bioinformatics methods. The expression levels of WARGsSig were measured by quantitative real-time polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). Tissue microarray (TMA) analysis was performed to determine the association between ventral anterior homeobox 2 (VAX2) expression and clinical outcomes of CRC patients by IHC. We also investigated the functional role and molecular mechanism of VAX2 using small interfering RNA (siRNA) in vitro. RESULTS The WARGsSig exhibited strong diagnostic accuracy and was an independent prognostic factor, with low-risk patients showing improved survival. It was also correlated with immune cell infiltration. VAX2, the gene with the highest hazard ratio in the signature, was overexpressed in CRC-TMA cohort and associated with poor prognosis. Functional experiments showed that VAX2 knockdown inhibited CRC cells proliferation, migration, and invasion, and induced apoptosis, while VAX2 overexpression reversed the effects. Mechanistic studies indicated that VAX2 cooperatively regulates downstream genes within Wnt signaling and axon guidance pathways to promote epithelial-mesenchymal transition (EMT). CONCLUSION The WARGsSig provides a potential tool for predicting diagnosis, prognosis, molecular subtypes, and immune context in CRC. These findings offer mechanistic insights and a foundation for future research, with promising implications for risk stratification and personalized treatment strategies.

PUBLICATION RECORD

CITATION MAP

EXTRACTION MAP

CLAIMS

  • No claims are published for this paper.

CONCEPTS

  • No concepts are published for this paper.

REFERENCES

Showing 1-52 of 52 references · Page 1 of 1

CITED BY

  • No citing papers are available for this paper.

Showing 0-0 of 0 citing papers · Page 1 of 1