Plexin Domain Containing 2, a Protein Specifically Expressed and Elevated in Human Pancreatic Cancer Tissue and Serum, Influences Cell Proliferation by Correlating With Cortactin.

[BACKGROUND] Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with limited treatment options. Plexin domain containing 2 (PLXDC2), a tumor endothelial marker, has been implicated in several cancers, but its role in PDAC remains unclear. This study aimed to investigate the role of PLXDC2 and its interaction with cortactin in PDAC.

[METHOD] PLXDC2 and cortactin expression levels were assessed by immunohistochemistry in human PDAC tissues. Serum PLXDC2 levels were measured using ELISA. PDAC cell lines were transfected with PLXDC2 siRNA. The effects of PLXDC2 knockdown on cortactin and oncogene expression, as well as cell proliferation, were evaluated using quantitative PCR, Western blotting, immunofluorescence, and proliferation assays. Computational modeling with AlphaFold3 predicted the 3D structure of the PLXDC2-cortactin complex and designed inhibitory peptide.

[RESULTS] PLXDC2 was overexpressed in PDAC tissues and serum, with an AUROC of 0.987 compared to healthy individuals. PLXDC2 co-expressed with cortactin in human PDAC tissues. In PDAC cells, PLXDC2 knockdown led to decreased cortactin expression, followed by a reduction of oncogene (c-myc and Oct4) expression and proliferation. Computational analysis predicted that the SH3 domain of cortactin binds to the PSI domain of PLXDC2. Peptide-mediated inhibition of the PLXDC2-cortactin binding, by targeting the SH3 domain of cortactin, led to a reduction of oncogenic and proliferative genes.

[CONCLUSIONS] PLXDC2 is a potential biomarker of PDAC diagnosis. Targeting the PLXDC2-cortactin interaction may offer a novel therapeutic strategy.