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| NR3C1蛋白在胃癌组织中的表达及其调控机制与临床意义 |
| Expression, Regulatory Mechanism, and Clinical Significance of NR3C1 Protein in Gastric Cancer Tissues |
| 投稿时间：2026-06-16 修订日期：2026-08-13 |
| DOI： |
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| 中文关键词: 胃癌 NR3C1蛋白 表达调控 甲基化 临床预后 |
| 英文关键词:Gastric cancer NR3C1 protein Expression regulation Methylation Clinical prognosis |
| 基金项目:邯郸市科学技术研究与发展计划项目（项目编号：23422083209） |
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| 中文摘要: |
| 目的 探讨核受体亚家族3C成员1(NR3C1)蛋白在胃癌中的表达与临床病理参数及预后的关系,明确其启动子甲基化调控机制及对胃癌细胞侵袭、迁移的影响,为胃癌的预后评估及精准治疗提供新的分子靶点和理论依据。方法 回顾性选取2020年1月至2021年2月期间我院收治的76例胃癌患者的临床资料。采用免疫组织化学法检测NR3C1蛋白阳性表达率,Western blot及实时荧光定量聚合酶链反应(qRT-PCR)法检测NR3C1蛋白及mRNA相对表达量；采用Kaplan-Meier法进行生存分析；多因素Cox回归分析影响胃癌患者预后的因素。结合甲基化特异性PCR及MethyLight定量检测NR3C1启动子区甲基化状态,利用胃癌细胞系MKN45进行功能回复实验,探索其表观遗传调控机制。结果 胃癌组织中NR3C1阳性表达率为68.42%(52/76),高于癌旁组织及正常胃组织15.79%(12/76),13.16%(10/76),差异具有统计学意义(χ2=42.182,48.052,P<0.001)。胃癌组织中NR3C1 mRNA相对表达量为(2.35±0.68),高于癌旁组织及正常胃组织的(0.89±0.24),(0.91±0.25),差异具有统计学意义(t=17.651,17.327,P<0.001)。低分化, TNM Ⅲ～Ⅳ期及有淋巴结转移患者胃癌组织中NR3C1阳性表达率显著高于中高分化组织,Ⅰ～Ⅱ期及无淋巴结转移患者,差异具有统计学意义(均P＜0.05)。NR3C1阳性组患者的中位总生存期为28.5个月,显著短于NR3C1阴性组的45.2个月,差异具有统计学意义(Log-rank χ2=12.897,P<0.001)。NR3C1阳性组患者的中位无进展生存期为16.8个月,显著短于NR3C1阴性组的32.4个月,差异具有统计学意义(Log-rank χ2=10.953,P=0.001)。NR3C1阳性(HR=2.314,95%CI:1.426～3.752,P=0.009),TNM Ⅲ～Ⅳ期(HR=1.987,95%CI:1.192～3.315,P=0.003)及有淋巴结转移(HR=1.865,95%CI:1.103～3.154,P=0.004)是影响胃癌患者预后的独立危险因素。胃癌组织中NR3C1启动子区甲基化率为23.68%(18/76),显著低于癌旁正常组织的60.53%(46/76),差异具有统计学意义(χ2=21.159,P<0.001)。胃癌组织中NR3C1 PMR为(6.14±1.18),显著低于癌旁正常组织的(36.47±6.02),差异具有统计学意义(t=43.102,P<0.001)。与NC组相比,5-AzaC处理后MKN45 细胞中NR3C1 mRNA及蛋白表达水平均显著上调。与NC组相比,oe-NR3C1组细胞侵袭和迁移能力显著增强,si-NR3C1组细胞侵袭和迁移能力显著减弱；NC+5-AzaC组细胞迁移和侵袭能力较NC组显著增强,且与 oe-NR3C1组趋势一致,而转染si?NR3C1敲低NR3C1基因表达后,5?AzaC所诱导的促迁移和侵袭作用被明显逆转。结论 NR3C1蛋白在胃癌组织中呈高表达,与分化程度、TNM分期、淋巴结转移有关,NR3C1启动子区低甲基化是其在胃癌中高表达的重要调控机制,且NR3C1高表达可促进胃癌细胞的侵袭和迁移,可作为评估胃癌患者不良预后的潜在生物标志物。 |
| 英文摘要: |
| Objective To investigate the expression of nuclear receptor subfamily 3 group C member 1 (NR3C1) protein in gastric cancer and relationship with clinicopathological parameters and prognosis, clarify its promoter methylation regulatory mechanism and its impact on the invasion and migration of gastric cancer cells, so as to provide new molecular targets and theoretical basis for the prognostic evaluation and precision therapy of gastric cancer. Methods Clinical data from 76 gastric cancer patients admitted to our hospital from January 2020 to February 2021 were retrospectively collected. IHC was used to detect the NR3C1 protein expression, and Western blot and qRT-PCR were used to detect the NR3C1 protein and mRNA expression. Survival analysis was performed using the Kaplan?Meier method, and prognostic factors were analyzed using multivariate Cox regression analysis. Methylation specific PCR (MSP) and MethylLight quantitative detection were used to detect NR3C1 promoter methylation status, and functional rescue experiments were performed using the gastric cancer cell line MKN45 to explore its epigenetic regulatory mechanism. Results The positive expression rate of NR3C1 in gastric cancer tissues was 68.42% (52/76), which was significantly higher than that in adjacent tissues (15.79%, 12/76) and normal gastric tissues (13.16%, 10/76) (χ2=42.182, 48.052, both P<0.001). qRT-PCR results showed that the relative expression level of NR3C1 mRNA in gastric cancer tissues was (2.35±0.68), which was significantly higher than that in adjacent tissues (0.89±0.24) and normal gastric tissues (0.91±0.25) (t=17.651, 17.327, both P<0.001). The positive expression rate of NR3C1 in gastric cancer tissues of patients with poorly differentiated tumors, TNM stage Ⅲ～Ⅳ, and lymph node metastasis was significantly higher than that in patients with moderately/well-differentiated tumors, stage Ⅰ～Ⅱ, and no lymph node metastasis (all P＜0.05). The median overall survival of patients in the NR3C1-positive group was 28.5 months, which was significantly shorter than that in the NR3C1-negative group (45.2 months) (Log-rank χ2=12.897, P<0.001). The median progression-free survival of patients in the NR3C1-positive group was 16.8 months, which was significantly shorter than that in the NR3C1-negative group (32.4 months) (Log-rank χ2=10.953, P=0.001). Multivariate Cox regression analysis showed that NR3C1 positivity (HR=2.314, 95%CI: 1.426～3.752, P=0.009), TNM stage Ⅲ～Ⅳ (HR=1.987, 95%CI: 1.192～3.315, P=0.003), and lymph node metastasis (HR=1.865, 95%CI: 1.103～3.154, P=0.004) were independent risk factors affecting the prognosis of gastric cancer patients. The methylation rate of the NR3C1 promoter region in gastric cancer tissues was 23.68% (18/76), which was significantly lower than that in adjacent normal tissues (60.53%, 46/76) (χ2=21.159, P<0.001). The PMR of NR3C1 in gastric cancer tissue was (6.14 ± 1.18), significantly lower than that in normal tissue adjacent to the cancer (36.47 ± 6.02), and the difference was statistically significant (t=43.102, P<0.001). Compared with the NC group, the cell invasion and migration ability of the oe-NR3C1 group was significantly enhanced, while the cell invasion and migration ability of the si-NR3C1 group was significantly weakened; The migration and invasion ability of cells in the NC+5-AzaC group was significantly enhanced compared to the NC group, and the trend was consistent with that of the oe-NR3C1 group. However, after transfection with si-NR3C1 and knocking down the NR3C1 gene expression, the migration and invasion promoting effect induced by 5 AzaC was significantly reversed. Conclusion The NR3C1 overexpression in gastric cancer tissues are associated with tumor differentiation, TNM stage and lymph node metastasis. Hypomethylation of the NR3C1 promoter region is an important regulatory mechanism for its high expression in gastric cancer. Moreover, NR3C1 can promote the invasion and migration of gastric cancer cells, so NR3C1 can be used as a potential biomarker for evaluating prognosis. |
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