# Molecular Interactions Between Dimethylated Arginine and the Nitric Oxide Axis Unveil Programmed Death-Ligand 1 (PD-L1) Signaling Signatures in Gastric Cancer

## TL;DR

This study explores how dimethylated arginine and nitric oxide interact to affect PD-L1 signaling in gastric cancer, revealing potential diagnostic and therapeutic targets.

## Contribution

The study identifies novel molecular interactions between dimethylated arginine, nitric oxide, and PD-L1 signaling in gastric cancer.

## Key findings

- Abnormal NO production and reduced mitochondrial DNA copy numbers were observed in gastric cancer patients.
- Significantly decreased levels of ADMA and increased arginase activity were found in gastric cancer patients.
- PD-L1 expression was higher in gastric cancer patients, while suboptimal PD-L1 was linked to disease control.

## Abstract

Background

Gastric cancer (GC) is one of the most common cancers globally. Programmed death cells, a cell-surface molecule, drive arginine dimethylation, disrupting nitric oxide (NO) production in peripheral tissues. Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis disruption depends on dimethylarginine dimethylaminohydrolase 1 (DDAH1) activity during metastasis in patients with severe gastritis, either synergizing with NO or inhibiting PD-1/PD-L1 activation in tumor growth. This study aimed to determine the arginine dimethylation process in conjunction with nitrosative stress, which dysregulates the PD-L1 axis in GC cells.

Methodology

A cross-sectional study was conducted utilizing real-time polymerase chain reaction for relative mRNA expressions, high-performance liquid chromatography for asymmetric dimethylarginine (ADMA)/symmetric dimethylarginine (SDMA) assays, and spectrophotometry for NO analysis. Statistical tools such as RStudio (version 2024.12.1) were used to conduct principal component analysis, heatmaps, and t-tests/analysis of variance or Mann-Whitney/Kruskal-Wallis tests after Shapiro-Wilk post-hoc tests in different groups (GC, disease control, and healthy control).

Results

We observed abnormal NO production and reduced mitochondrial DNA copy numbers in GC patients. Significantly decreased levels of ADMA and excessive influx of arginase activity were determined in GC patients. PD-L1 expression was significantly higher in GC patients, while suboptimal PD-L1 expression was associated with disease control. The abnormal influx of dimethylated arginine and matrix metalloproteinase-7 (MMP-7) was associated with and linked to NO production levels. Their association could be with the nitrigenic pathway and with possible mechanisms for damaging cell-surface molecules in GC.

Conclusions

Overall, the disrupted ADMA-SDMA balance and Ca++ permeability impair the regulation of claudin-4, MMP-7, and PD1/PD-L1 in GC patients. These variables hold promise as diagnostic and therapeutic targets for improved GC management.