摘要
Background:It is of great clinical significance to further explore new strategies and potential combined therapeutic targets for gastric cancer.This study aimed to investigate the synthetic lethal effect of RBBP8 molecular intervention combined with a poly ADP ribose polymerase(PARP)inhibitor in non-BRCA mutant gastric cancer and clarify the mechanism by which RBBP8 regulates homologous recombination repair.Methods:The role of RBBP8 in DNA damage repair was observed using bioinformatic analysis,western blot analysis,and immunofluorescence.The synthetic lethal effect was verified using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,inner salt(MTS)and flow cytometry apoptosis experiments.Results:Among the patients with gastric cancer treated with chemotherapy,the prognosis of patients with high RBBP8 expression levels was worse(homologous recombination[HR]=1.54,p=0.028).RBBP8 knockdown induced DNA damage and had a synergistic effect with PARP inhibitor treatment on cell viability inhibition and cell apoptosis in AGS(generic code for human gastric adenocarcinoma cells)(t=11.154,p<0.001)and N87(t=6.362,p<0.001)cells.RBBP8 knockdown inhibited RAD51 activation and DNA terminal excision in homologous recombination repair.Conclusion:RBBP8 is involved in homologous recombination repair,and molecular intervention into RBBP8 could achieve a synthetic lethal effect with PARP inhibitor treatment in gastric cancer cells.
