Zhu Zhipeng, Lin Sihao, Wu Xiaofang, Xu Jiuhua, Li Lulu, Ye Weipeng, Li Jiayi, Huang Zhengjie
Department of Gastrointestinal Surgery, Xiamen Cancer Center, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People's Republic of China.
Department of Clinical Medicine, Fujian Medical University, Fuzhou, Fujian 350004, People's Republic of China.
Onco Targets Ther. 2021 Jan 22;14:623-636. doi: 10.2147/OTT.S276168. eCollection 2021.
Cisplatin is a vital chemotherapy regimen for gastric cancer (GC), while partial response is observed (approximately 40%) because of drug resistance. Thus, it is urgent to improve drug sensitivity to improve the therapeutic effect of cisplatin on GC.
The study was performed to explore the synergistic effect of decitabine and cisplatin in GC.
Cancer and matched adjacent tissues from patients with GC were obtained and quantitative real-time PCR (qRT-PCR), Western blot and immunohistochemistry were performed to evaluate Sox2 expression level. Methylation-specific PCR (MSP) was performed to assess the effect of 5-aza-2'-deoxycytidine (5-Aza-CdR) on Sox2 promoter. Cell proliferation assay, scratch-wound migration assay and Transwell invasion ability were performed to assess the effect of 5-Aza-CdR on proliferation, migration and invasion ability. Meantime, the effect of 5-Aza-CdR was also investigated in gastric cell lines BGC-823 and nude mouse xenograft tumor model. Finally, the anti-cancer effect of decitabine, cisplatin and their combination treatment were investigated in a BGC-823 and nude mouse xenograft tumor model, Sox2 methylation level, Sox2 expression of BGC-823 and xenograft tumors were analyzed by MSP, qRT-PCR and Western blot.
Sox2 expression was significantly associated with different differentiated degrees, depth of invasion (0.0011), lymph node metastasis (0.0013), and TNM stage (0.0002). Next, methylation inhibitor 5-Aza-CdR restored Sox2 expression to promote proliferation, migration and invasion in vitro and in vivo. Finally, cisplatin and decitabine was found to be synergistic to inhibit proliferation of xenograft tumors. Likewise, cisplatin and decitabine were also synergistic to induce Sox2 DNA demethylation to promote Sox2 mRNA and protein expression in BGC-823 and xenograft tumors.
Cisplatin and decitabine could be synergistic to induce Sox2 DNA demethylation to promote expression of the Sox2 gene, which exerted an anti-tumor effect on GC. It may suggest an insight for innovative therapeutics of GC.
顺铂是胃癌（GC）重要的化疗方案，但由于耐药性，仅观察到部分缓解（约40%）。因此，迫切需要提高药物敏感性以改善顺铂对GC的治疗效果。
本研究旨在探讨地西他滨与顺铂在GC中的协同作用。
获取GC患者的癌组织及配对的癌旁组织，采用定量实时聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法和免疫组织化学法评估Sox2表达水平。采用甲基化特异性聚合酶链反应（MSP）评估5-氮杂-2'-脱氧胞苷（5-Aza-CdR）对Sox2启动子的影响。进行细胞增殖实验、划痕伤口迁移实验和Transwell侵袭实验，评估5-Aza-CdR对增殖、迁移和侵袭能力的影响。同时，在胃癌细胞系BGC-823和裸鼠异种移植瘤模型中研究5-Aza-CdR的作用。最后，在BGC-823和裸鼠异种移植瘤模型中研究地西他滨、顺铂及其联合治疗的抗癌效果，通过MSP、qRT-PCR和蛋白质免疫印迹法分析BGC-823和异种移植瘤的Sox2甲基化水平、Sox2表达。
Sox2表达与不同分化程度、浸润深度（0.0011）、淋巴结转移（0.0013）及TNM分期（0.0002）显著相关。接下来，甲基化抑制剂5-Aza-CdR恢复Sox2表达，在体外和体内促进增殖、迁移和侵袭。最后，发现顺铂和地西他滨具有协同作用，可抑制异种移植瘤的增殖。同样，顺铂和地西他滨还具有协同作用，可诱导Sox2 DNA去甲基化，促进BGC-823和异种移植瘤中Sox2 mRNA和蛋白表达。
顺铂和地西他滨可协同诱导Sox2 DNA去甲基化，促进Sox2基因表达，对GC发挥抗肿瘤作用。这可能为GC的创新治疗提供思路。
