2026 年第 4 期 第 21 卷

胃癌患者斯坦尼钙调节蛋白2表达水平及其对免疫治疗耐药性的预测价值

Expression level of Stanniocalcin 2 in gastric cancer patients and its predictive value for resistance to immunotherapy

作者：林惠灵孟加榕禹乐朱启淦

英文作者：Lin Huiling Meng Jiarong Yu Le Zhu Qigan

单位：第九〇九医院（厦门大学附属东南医院）病理科，漳州363000

英文单位：Department of Pathology the 909th Hospital (Dongnan Hospital of Xiamen University) Zhangzhou 363000 China

关键词：胃癌；斯坦尼钙调节蛋白2；免疫治疗；耐药性

英文关键词：Gastriccancer;Stanniocalcin2;Immunotherapy;Drugresistance

• 摘要：

• 目的 探讨胃癌患者斯坦尼钙调节蛋白2（STC2）表达水平及其对免疫治疗耐药性的预测价值。方法 选取2022年4月至2024年4月第九〇九医院收治的胃癌患者148例为研究对象，采用逆转录实时荧光定量聚合酶链反应检测胃癌组织及配对癌旁组织（距肿瘤边缘≥5 cm的非肿瘤胃黏膜组织）中STC2 mRNA相对表达量；通过免疫组织化学法检测STC2蛋白表达，结合染色强度和阳性细胞比例将患者分为STC2高表达组（90例）和低表达组（58例）。收集患者临床病理资料，并观察免疫治疗耐药情况。采用受试者工作特征（ROC）曲线评估STC2表达水平对免疫治疗耐药性的预测效能，相关性热图分析STC2表达与肿瘤免疫微环境指标［CD+8 T细胞、CD+4 T细胞、B细胞浸润比例，程序性死亡受体1（PD-1）在T细胞中的阳性率，调节性T细胞（Treg，以FOXP3+为标志物）的浸润比例、巨噬细胞（以CD68+为标志物）的浸润比例以及肿瘤细胞表面程序性死亡受体配体1(PD-L1)的阳性率］的关联。结果  胃癌组织中STC2 mRNA相对表达量为（2.7±0.7），显著高于癌旁组织（1.0±0.3），差异有统计学意义（t＝27.035，P<0.001）；胃癌组织中STC2阳性表达率（58.1%）较癌旁组织阳性表达率（29.7%）高（χ2＝24.196，P<0.001）。高表达组TNM分期中Ⅳ期、浸润浆膜层及浆膜外、有淋巴结转移的患者占比均高于低表达组（均P＜0.05）。148例患者中44例出现免疫治疗耐药，其中高表达组免疫治疗耐药率高于低表达组［36.7%(33/90)比19.0%（11/58）］（χ2＝5.290，P=0.021）。ROC曲线显示：STC2表达水平预测胃癌患者免疫治疗耐药性的曲线下面积为0.908（95%置信区间：0.850～0.949），敏感度和特异度分别为81.82%和92.30%。相关性热图分析结果显示，胃癌组织中STC2表达水平与CD+8 T细胞、CD+4 T细胞及B细胞的浸润比例、PD-1在T细胞中的阳性率呈显著负相关（均P<0.001），与Treg（FOXP3+）的浸润比例、巨噬细胞（CD+68）的浸润比例以及肿瘤细胞表面PD-L1的阳性率呈显著正相关（均P<0.001）。结论 胃癌组织中STC2表达水平显著升高，与肿瘤浸润深度、淋巴结转移及晚期分期相关；高表达STC2的胃癌患者免疫治疗耐药率更高，STC2可作为预测免疫治疗耐药性的有效生物标志物，其机制可能与调控肿瘤免疫微环境相关。

• Objective To investigate the expression level of Stanniocalcin 2 (STC2) in gastric cancer patients and its predictive value for resistance to immunotherapy. Methods A total of 148 gastric cancer patients admitted to the 909th Hospital of the Joint Logistics Support Force of the Chinese People′s Liberation Army from April 2022 to April 2024 were enrolled as research subjects. Reverse transcription real-time fluorescent quantitative polymerase chain reaction was used to detect the relative expression of STC2 mRNA in gastric cancer tissues and paired paracancerous tissues (non-tumor gastric mucosal tissues ≥5 cm from the tumor edge). Immunohistochemistry was performed to detect STC2 protein expression, and patients were divided into the high STC2 expression group (90 cases) and low STC2 expression group (58 cases) according to staining intensity and the proportion of positive cells. The clinicopathological data of patients were collected, and the occurrence of immunotherapy resistance was observed. Receiver operating characteristic (ROC) curve was used to evaluate the predictive efficacy of STC2 expression level for immunotherapy resistance. Correlation heatmap was used to analyze the association between STC2 expression and tumor immune microenvironment indicators, including the infiltration ratios of CD+8 T cells, CD+4 T cells and B cells, the positive rate of programmed cell death protein 1 (PD-1) in T cells, the infiltration ratios of regulatory T cells (Treg, marked by FOXP3+) and macrophages (marked by CD+68), as well as the positive rate of programmed cell death ligand 1 (PD-L1) on the surface of tumor cells. Results The relative expression of STC2 mRNA in gastric cancer tissues was (2.7±0.7), which was significantly higher than that in paracancerous tissues (1.0±0.3), with a statistically significant difference (t=27.035, P<0.001). The positive expression rate of STC2 in gastric cancer tissues (58.1%) was higher than that in paracancerous tissues (29.7%)(χ2=24.196, P<0.001). The proportions of patients with TNM stage Ⅳ, serosal and extra-serosal infiltration, and lymph node metastasis in the high expression group were all higher than those in the low expression group (all P<0.05). Among the 148 patients, 44 developed immunotherapy resistance, and the resistance rate in the high expression group was higher than that in the low expression group ［36.7%(33/90) vs 19.0%(11/58)］(χ2=5.290, P=0.021). ROC curve analysis showed that the area under the curve of STC2 expression level for predicting immunotherapy resistance in gastric cancer patients was 0.908 (95% confidence interval: 0.850-0.949), with a sensitivity of 81.82% and a specificity of 92.30%. Correlation heatmap analysis revealed that STC2 expression level in gastric cancer tissues was significantly negatively correlated with the infiltration ratios of CD+8 T cells, CD+4 T cells and B cells as well as the positive rate of PD-1 in T cells (all P<0.001), and significantly positively correlated with the infiltration ratios of FOXP3+ Treg cells and CD+68 macrophages as well as the positive rate of PD-L1 on the surface of tumor cells (all P<0.001). Conclusion The expression level of STC2 is significantly elevated in gastric cancer tissues, which is associated with tumor invasion depth, lymph node metastasis and advanced clinical stage. Gastric cancer patients with high STC2 expression have a higher rate of immunotherapy resistance, and STC2 can serve as an effective biomarker for predicting immunotherapy resistance, whose mechanism may be related to the regulation of tumor immune microenvironment.