Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Department of Obstetrics and Gynecology, Zhongshan Hospital, Shanghai 200032, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Nov 25;55(11):1784-1796. doi: 10.3724/abbs.2023119.
Currently, platinum-containing regimens are the most commonly used regimens for advanced gastric cancer patients, and chemotherapy resistance is one of the main reasons for treatment failure. Thus, it is important to reveal the mechanism of oxaliplatin resistance and to seek effective intervention strategies to improve chemotherapy sensitivity, thereby improving the survival and prognosis of gastric cancer patients. To understand the molecular mechanisms of oxaliplatin resistance, we generate an oxaliplatin-resistant gastric cancer cell line and conduct assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) for both parental and oxaliplatin-resistant AGS cells. A total of 3232 genomic regions are identified to have higher accessibility in oxaliplatin-resistant cells, and DNA-binding motif analysis identifies JUNB as the core transcription factor in the regulatory network. JUNB is overexpressed in oxaliplatin-resistant gastric cancer cells, and its upregulation is associated with poor prognosis in gastric cancer patients, which is validated by our tissue microarray data. Moreover, chromatin immunoprecipitation sequencing (ChIP-seq) analysis reveals that JUNB binds to the transcriptional start site of key genes involved in the MAPK signaling pathway. Knockdown of inhibits the MAPK signaling pathway and restores sensitivity to oxaliplatin. Combined treatment with the ERK inhibitor piperlongumine or MEK inhibitor trametinib effectively overcomes oxaliplatin resistance. This study provides evidence that JUNB mediates oxaliplatin resistance in gastric cancer by activating the MAPK pathway. The combination of MAPK inhibitors with oxaliplatin overcomes resistance to oxaliplatin, providing a promising treatment opportunity for oxaliplatin-resistant gastric cancer patients.
目前，含铂方案是晚期胃癌患者最常用的方案，化疗耐药是治疗失败的主要原因之一。因此，揭示奥沙利铂耐药的机制，寻求有效的干预策略以提高化疗敏感性，从而改善胃癌患者的生存和预后至关重要。为了了解奥沙利铂耐药的分子机制，我们生成了奥沙利铂耐药的胃癌细胞系，并对亲本和奥沙利铂耐药的 AGS 细胞进行转座酶可及染色质测序（ATAC-seq）和 RNA 测序（RNA-seq）分析。共鉴定出 3232 个基因组区域在奥沙利铂耐药细胞中具有更高的可及性，DNA 结合基序分析确定 JUNB 为调控网络中的核心转录因子。JUNB 在奥沙利铂耐药的胃癌细胞中过表达，并且其上调与胃癌患者的不良预后相关，这通过我们的组织微阵列数据得到了验证。此外，染色质免疫沉淀测序（ChIP-seq）分析表明，JUNB 结合到参与 MAPK 信号通路的关键基因的转录起始位点。抑制的敲低抑制了 MAPK 信号通路并恢复了对奥沙利铂的敏感性。与 ERK 抑制剂 piperlongumine 或 MEK 抑制剂 trametinib 联合治疗可有效克服奥沙利铂耐药性。这项研究提供了证据表明，JUNB 通过激活 MAPK 通路介导胃癌中的奥沙利铂耐药性。MAPK 抑制剂与奥沙利铂的联合应用克服了奥沙利铂耐药性，为奥沙利铂耐药的胃癌患者提供了有前途的治疗机会。
