PLXND1 from the Plexins family is a prognostic factor promoting colon cancer invasion and metastasis.

[OBJECTIVES] To elucidate the expression profile, immune infiltration, prognostic value, and role of Plexins in Colonic Adenocarcinoma (COAD).

[METHODS] The levels of the Plexins family members in COAD were verified, and their effect on clinical characteristics, immune infiltration, and prognosis were explored by The Cancer Genome Atlas (TCGA), Expression Atlas, and Human Protein Atlas (HPA) databases. The core molecule of Plexins, PLXND1, was screened and validated in COAD by qRT-PCR, immunohistochemistry, wound healing, transwell, immunofluorescence, western blotting, immunoprecipitation, and animal experiments.

[RESULTS] The PLXNA1/PLXNA3/PLXNA4/PLXNB1/PLXND1 levels were increased in COAD samples, whereas the levels of PLXNA2/PLXNB3/PLXNC1 were reduced. High PLXNA3/PLXNA4/PLXNB3/PLXND1 levels were related to the higher lymph node stage of COAD patients. Most Plexin levels were prominently associated with the infiltration of T cell regulators, macrophage M0, and eosinophils in COAD samples. High PLXNA3/PLXNB3/PLXND1 levels were interrelated with poor overall survival of COAD patients, and PLXND1 was a novel independent prognostic indicator. Furthermore, the PLXND1-associated differential molecular regulatory networks were analyzed, and the expression of PLXND1 was markedly increased in COAD tissues and lymph node-positive COAD patients. Mechanistically, PLXND1 promoted COAD cell invasion, metastasis, and epithelial-mesenchymal transition (EMT) ability by binding and modulating Notch3 signaling.

[CONCLUSIONS] Data mining revealed the crucial roles of the Plexin family in COAD, especially in clinical indicators, immune infiltration, and prognosis of COAD patients. PLXND1, as an independent prognostic biomarker, enabled COAD cell invasion, metastasis and EMT by binding and modulating Notch3 signaling.