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

## TL;DR

This study explores how PVR gene expression predicts colorectal cancer relapse and identifies potential immune checkpoint inhibitors through virtual screening.

## Contribution

The study identifies PVR as a novel prognostic biomarker for CRC relapse and proposes potential PVR/TIGIT interface binders.

## Key findings

- PVR gene is significantly upregulated in relapsed CRC patients and correlates with poor clinical parameters.
- Virtual screening identified 106 natural compounds as potential PVR/TIGIT binders, with one compound showing favorable interactions.
- Elevated PVR levels are associated with a 2.16-fold increased likelihood of relapse in CRC patients.

## Abstract

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 (PVR)/TIGIT binders. PVR 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 PVR 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 PVR levels were 2.16 times more likely to relapse than those with low PVR expression (p = 0.039). Virtual screening identified 106 natural compounds as potential binders at the PVR/TIGIT interface. Molecular docking and molecular dynamics simulations identified three binders that exhibit favorable interactions with PVR, with ZINC001848443492 emerging as the most promising. The results underscore the potential role of PVR 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.

Workflow diagram showing five steps in cancer research: 1. Data acquisition with icons of a researcher and sequencing equipment, 2. Colorectal cancer patient stratification by relapse status using human figure icons, 3. Genetic and epigenetic screening displayed by a heatmap of gene expression, 4. Identification of PVR as a therapeutic target with violin and survival plots, 5. Molecular docking and dynamics simulation illustrated by a protein-ligand structure and a line graph comparing RMSD values.