目的 基于核因子-κB（nuclear factor-κB，NF-κB）/SNAIL通路探讨密点麻蜥Eremias multiocellata不同部位联合顺铂（cisplatin，DDP）对胃癌裸鼠顺铂耐药模型的干预机制。方法 将36只BALB/c裸鼠于右侧腋窝sc MKN45/DDP细胞悬液制备胃癌裸鼠耐药模型，造模成功后随机分为模型组、DDP组、密点麻蜥头部＋DDP组、四肢＋DDP组、躯干＋DDP组和尾部＋DDP组，每组6只。除模型组外，其余各组给予相应药物治疗4周。MTT法检测MKN45/DDP细胞的耐药性；检测各组肿瘤体积及抑瘤率；苏木素-伊红（HE）染色观察各组肿瘤组织病理变化；免疫组化法检测各组肿瘤组织黏蛋白1（Mucin 1，MUC1）表达；Western blotting检测各组肿瘤组织中NF-κB/SNAIL通路相关蛋白、E-钙黏附蛋白（E-cadherin）及P-糖蛋白（P-glycoprotein，P-gp）、多药耐药蛋白1（multidrug resistance-associated protein 1，MRP1）、肺耐药蛋白（lung resistant protein，LRP）表达；TUNEL检测各组肿瘤组织细胞凋亡情况。结果 与MKN45细胞相比，MKN45/DDP细胞对顺铂的耐药性相对较强，其半数抑制浓度（half inhibitory concentration，IC₅₀）和耐药指数分别为0.671 μg/mL、1.973。与模型组比较，各给药组肿瘤体积均显著缩小（P<0.05），以尾部＋DDP组抑瘤率最高；肿瘤细胞排列稀疏，细胞核呈不同程度缩小或破裂；肿瘤组织p-p65、SNAIL、P-gp、MRP1、LRP和MUC1蛋白表达水平均显著降低（P<0.05、0.01），E-cadherin蛋白表达水平均显著升高（P<0.05、0.01），细胞凋亡率均显著升高（P<0.05、0.01），以尾部＋DDP组最为明显。结论 密点麻蜥不同部位联合DDP可调控NF-κB/SNAIL通路，逆转荷瘤裸鼠胃癌顺铂耐药，以尾部＋DDP组增敏提效作用最佳。

Objective To explore the intervention mechanism of different parts of Eremias multiocellata combined cisplatin (DDP) on cisplatin-resistant model of gastric cancer in nude mice based on nuclear factor-κB (NF-κB)/SNAIL pathway. Methods Thirty-six BALB/c nude mice were subcutaneously injected with MKN45/DDP cells suspension in the right armpit to establish a drug-resistant model of gastric cancer. After successful modeling, mice were randomly divided into model group, DDP group, head + DDP group, limbs + DDP group, trunk + DDP group and tail + DDP group, with six mice in each group. Except the model group, the other groups were given corresponding drugs for four weeks. Drug resistance of MKN45/DDP cells were detected by MTT assay. The tumor volume and tumor inhibition rate of each group were detected. HE staining was used to observe the pathological changes of tumor tissues in each group. Immunohistochemical method was used to detect Mucin 1 (MUC1) expression in tumor tissues of each group. Western blotting was used to detect expressions of NF-κB/SNAIL pathway related proteins, E-cadherin, P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and lung resistance protein (LRP) in tumor tissues of each group. TUNEL was used to detect the apoptosis of tumor tissue in each group. Results Compared with MKN45 cells, MKN45/DDP cells were relatively resistant to cisplatin, its half inhibitory concentration (IC₅₀) and drug resistance index were 0.671 μg/mL and 1.973, respectively. Compared with model group, tumor volume in each group was significantly reduced (P < 0.05), and the tumor inhibition rate in tail + DDP group was the highest. The tumor cells were sparsely arranged, and the nuclei were reduced or ruptured to varying degrees. The expressions of p-p65, SNAIL, P-gp, MRP1, LRP and MUC1 protein in tumor tissues were significantly decreased (P < 0.05, 0.01), while E-cadherin protein expression was significantly increased (P < 0.05, 0.01), and apoptosis rate was significantly increased (P < 0.05, 0.01), tail + DDP group was the most obvious. Conclusion The combination of different parts of E. multiocellata with DDP can regulate NF-κB/SNAIL pathway and reverse cisplatin resistance of gastric cancer in nude mice bearing tumor, and tail + DDP group has the best sensitization effect.

R285.5

宁夏自然科学基金重点项目（2021AAC02014）；国家自然科学基金资助项目（82260916）