Mechanism of RBBP8-mediated homologous recombination repair in gastric cancer synthetic lethal

Q1 Medicine Chronic Diseases and Translational Medicine Pub Date : 2023-06-22 DOI:10.1002/cdt3.75

Yang Yu, Shuxia Wang, Yanhua Yin, Guangsheng Wang

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Abstract

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.

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rbbp8介导的同源重组修复在胃癌合成致死中的作用机制

背景进一步探索胃癌的新策略和潜在的联合治疗靶点具有重要的临床意义。本研究旨在探讨RBBP8分子干预联合聚ADP核糖聚合酶(PARP)抑制剂对非brca突变型胃癌的合成致死作用，阐明RBBP8调控同源重组修复的机制。方法采用生物信息学分析、western blot分析和免疫荧光法观察RBBP8在DNA损伤修复中的作用。采用3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺苯基)- 2h -四氮唑、内盐(MTS)和流式细胞术细胞凋亡实验验证了合成致死效应。结果在接受化疗的胃癌患者中，RBBP8高表达患者预后较差(同源重组[HR] = 1.54, p = 0.028)。RBBP8敲低诱导DNA损伤，并与PARP抑制剂处理在AGS(人胃腺癌细胞通用代码)(t = 11.154, p < 0.001)和N87细胞(t = 6.362, p < 0.001)细胞活力抑制和细胞凋亡方面具有协同作用。RBBP8敲低抑制同源重组修复中RAD51的激活和DNA末端切除。结论RBBP8参与同源重组修复，分子干预RBBP8与PARP抑制剂治疗胃癌细胞可达到合成致死作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Chronic Diseases and Translational Medicine Medicine-General Medicine

CiteScore

6.70

自引率

0.00%

发文量

195

审稿时长

35 weeks

期刊介绍： This journal aims to promote progress from basic research to clinical practice and to provide a forum for communication among basic, translational, and clinical research practitioners and physicians from all relevant disciplines. Chronic diseases such as cardiovascular diseases, cancer, diabetes, stroke, chronic respiratory diseases (such as asthma and COPD), chronic kidney diseases, and related translational research. Topics of interest for Chronic Diseases and Translational Medicine include Research and commentary on models of chronic diseases with significant implications for disease diagnosis and treatment Investigative studies of human biology with an emphasis on disease Perspectives and reviews on research topics that discuss the implications of findings from the viewpoints of basic science and clinical practic.

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