Objective To investigate the correlation between RYR1 gene and the development of gastric cancer, as well as the mechanism of RYR1 in promoting the progression of gastric cancer.

Methods We analyzed gastric cancer data from TCGA and conducted high-throughput targeted sequencing and transcriptome sequencing on 81 gastric cancer tissue samples at Tianjin Medical University Cancer Institute & Hospital (TJMUCH) from December 2010 to December 2012. We collected clinicopathological data, compared the correlation between RYR1 mutations and expression levels, and analyzed the impact of RYR1 on the prognosis of patients with gastric cancer. Additionally, we explored the underlying molecular mechanism to study its role in promoting the development of gastric cancer by generating stable cell lines overexpressing RYR1.

Results In TCGA gastric cancer patients, the mutation rate of RYR1 in Asian population was higher than that in others population (12.68% vs. 8.13%). In gastric cancer patients from TJMUCH, RYR1 mutations ranked ninth in frequency, with a mutation rate of 33.33%. Mutations in RYR1 were negatively correlated with RYR1 expression (P=0.006 9, P<0.000 1). Patients with high RYR1 expression had significantly worse overall survival than those with low RYR1 expression (P=0.009 0, P=0.042 0). Overexpression of RYR1 promoted proliferation, migration, invasion and reduced apoptosis of gastric cancer cell lines. Moreover, RYR1 overexpression was associated with decreased sensitivity to chemotherapeutic drugs in gastric cancer cells. Inhibiting RYR1-mediated calcium over-release could suppress malignant behaviors and reverse chemoresistance.

Conclusions RYR1 had a high mutation rate in Asian gastric cancer patients and a significantly negative correlation with RYR1 mRNA levels. High RYR1 expression serves as a novel prognostic predictive marker for gastric cancer. RYR1 overexpression promoted malignant progression of gastric cancer and chemoresistance by increasing the release of calcium ions from the endoplasmic reticulum. Thus, RYR1 inhibition can reduce the proliferation, migration, and invasion of gastric cancer cells and reverse chemoresistance, which highlights potential combination therapies for gastric cancer.