# NR4A1 expression aberrations contribute to radiotherapy resistance in gastric cancer

## TL;DR

This study shows that abnormal NR4A1 gene expression makes gastric cancer cells resistant to radiotherapy, and restoring NR4A1 can increase sensitivity to radiation treatment.

## Contribution

The study identifies NR4A1 as a novel gene linked to radiotherapy resistance in gastric cancer and demonstrates its therapeutic potential.

## Key findings

- NR4A1 expression is reduced in radioresistant gastric cancer cells.
- Overexpression of NR4A1 increases radiation sensitivity in resistant cells.
- NR4A1 overexpression inhibits tumor growth and metastasis in animal models after irradiation.

## Abstract

Gastric cancer (GC) is a common and life-threatening malignancy. It is often diagnosed at advanced stages. A major challenge in treatment is the development of radiotherapy resistance. This resistance significantly reduces the effectiveness of therapy. Therefore, our objective is to pinpoint genes linked to the resistance against radiotherapy in gastric cancer. The NR4A1 expression exhibited abnormalities in radioresistant gastric cancer cells, specifically MKN45-R and AGS-R cells, in comparison to their respective parental cells. Through high-throughput sequencing, we screened these cells and utilized quantitative reverse transcription-polymerase chain reaction analysis (qRT-PCR) to quantify NR4A1 expression. Functional analyses of NR4A1 in GC radioresistance were conducted by overexpressing NR4A1 in both MKN45-R and AGS-R cells, as well as their parental counterparts. Finally, the clinical relevance of NR4A1 in GC was confirmed through animal experiments. The expression of NR4A1 was significantly reduced in radioresistant cells, namely MKN45-R and AGS-R, as opposed to their parental counterparts. Overexpressing NR4A1 in MKN45-R and AGS-R cells resulted in heightened sensitivity to radiation. Additionally, NR4A1 overexpression exerted inhibitory effects on the growth and metastasis of GC tissues in animal models following irradiation (IR). Our observations indicate that NR4A1 plays a crucial role in enhancing the radiation sensitivity of gastric cancer cells, underscoring the therapeutic potential of NR4A1 in GC treatment.

The online version contains supplementary material available at 10.1038/s41598-025-20348-4.