Poliovirus receptor (PVR) expression as a predictor of relapse in colorectal cancer: bioinformatics and virtual screening

Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies worldwide. Despite advancements in CRC treatment strategies in recent years, disease recurrence remains a major problem; relapsed patients have a poorer prognosis and higher mortality risk. Several factors have been associated with CRC relapse. However, the role of immune checkpoints in CRC recurrence remains elusive. In this work, we aimed to investigate immune checkpoint genes correlated with recurrence in CRC, evaluate their potential as prognostic biomarkers, and identify promising immune checkpoint inhibitors through molecular docking and molecular dynamics simulations. Clinical, genetic, and epigenetic data of relapsed and relapse-free CRC patients in the Cancer Genome Atlas were retrieved from the cBioportal database and evaluated. Subsequently, molecular docking and molecular dynamics simulations studies were conducted to identify suitable poliovirus receptor (<i>PVR</i>)/TIGIT binders. <i>PVR</i> is a ligand for TIGIT and competes with CD226. The crystal structure used for docking was obtained from the Protein Data Bank (PDB ID: 3UDW). Using this investigative approach, clinical parameters data revealed that among immune checkpoint genes, the <i>PVR</i> gene was significantly upregulated in relapsed patients. That upregulation was strongly correlated with diagnosis age, Aneuploidy, fraction genome alterations, and mutation count. Furthermore, free survival analysis showed that patients exhibiting elevated <i>PVR</i> levels were 2.16 times more likely to relapse than those with low <i>PVR</i> expression (<i>p</i> = 0.039). Virtual screening identified 106 natural compounds as potential binders at the <i>PVR</i>/TIGIT interface. Molecular docking and molecular dynamics simulations identified three binders that exhibit favorable interactions with <i>PVR</i>, with ZINC001848443492 emerging as the most promising. The results underscore the potential role of <i>PVR</i> as a prognostic biomarker for relapse in CRC. Future studies, including TIGIT-PVR blockade assays and assessments of the impact of predicted PVR/TIGIT interface binders on T cell function, are necessary to validate this study's findings.