Yu Yang, Wang Shuxia, Yin Yanhua, Wang Guangsheng
Department of Gastroenterology Beijing Friendship Hospital Beijing China.
Department of Oncology Beijing Aviation General Hospital Beijing China.
Chronic Dis Transl Med. 2023 Jun 22;9(3):250-257. doi: 10.1002/cdt3.75. eCollection 2023 Sep.
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.
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.
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, = 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) ( = 11.154, < 0.001) and N87 ( = 6.362, < 0.001) cells. RBBP8 knockdown inhibited RAD51 activation and DNA terminal excision in homologous recombination repair.
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.
进一步探索胃癌新的治疗策略和潜在联合治疗靶点具有重要临床意义。本研究旨在探讨RBBP8分子干预联合聚腺苷酸二磷酸核糖聚合酶（PARP）抑制剂在非BRCA突变型胃癌中的合成致死效应，并阐明RBBP8调控同源重组修复的机制。
采用生物信息学分析、蛋白质免疫印迹分析和免疫荧光观察RBBP8在DNA损伤修复中的作用。通过3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑内盐（MTS）和流式细胞术凋亡实验验证合成致死效应。
在接受化疗的胃癌患者中，RBBP8表达水平高的患者预后较差（同源重组[HR]=1.54，=0.028）。RBBP8基因敲低诱导DNA损伤，并与PARP抑制剂处理对AGS（人胃腺癌细胞通用代码）（=11.154，<0.001）和N87（=6.362，<0.001）细胞的细胞活力抑制和细胞凋亡具有协同作用。RBBP8基因敲低抑制同源重组修复中的RAD51激活和DNA末端切除。
RBBP8参与同源重组修复，对RBBP8进行分子干预可与PARP抑制剂处理在胃癌细胞中产生合成致死效应。
