Gong Xiaodi, Wang Zhifeng, You Jiahao, Gao Jinghai, Chen Kun, Chu Jing, Sui Xiaoxin, Dang Jianhong, Liu Xiaojun
Department of Gynecology and Obstetrics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
Discov Oncol. 2024 Sep 12;15(1):433. doi: 10.1007/s12672-024-01315-3.
The occurrence and progression of tumors are linked to the process of pyroptosis. However, the precise involvement of pyroptosis-associated genes (PRGs) in endometrial cancer (EC) remains uncertain. 29 PRGs were identified as being either up-regulated or down-regulated in EC. PRGs subgroup analysis demonstrated distinct survival outcomes and diverse responses to chemotherapy and immune checkpoint blockade therapy. A higher expression of GPX4 and NOD2, coupled with lower levels of CASP6, PRKACA, and NLRP2, were found to be significantly associated with higher overall survival (OS) rates (p < 0.05). Conversely, lower expression of NOD2 was linked to lower progression-free survival (p = 0.021) and advanced tumor stage(p = 0.0024). NOD2, NLRP2, and TNM stages were identified as independent prognostic factors (p < 0.001). The LASSO prognostic model exhibited a notable decrease in OS among EC patients in the high-risk score group (ROC-AUC: 0.799, p = 0.00644). Furthermore, NOD2 displayed a positive correlation with the infiltration of immune cells and the expression of immune checkpoints (p < 0.001). GPX4 and CASP6 are significantly associated with TMB and MSI (R = 0.39; R = 0.23). Additionally, a substantial upregulation of NOD2 was confirmed in both EC cells and tissue, indicating a positive relationship between advanced TNM stage (p < 0.0001) and infiltration of M1 phenotype macrophages. Nonetheless, its impact on patient OS did not reach statistical significance (p = 0.141). Our findings have contributed to the advancement of a prognostic model for EC patients. NOD2 receptor-mediated pyroptosis mechanism potentially regulates tumor immunity and promotes the transformation of macrophages from the M2 phenotype to the M1 phenotype, which significantly impacts the progression of EC.
肿瘤的发生和进展与细胞焦亡过程相关。然而，细胞焦亡相关基因（PRGs）在子宫内膜癌（EC）中的具体作用仍不明确。研究确定了29个在EC中上调或下调的PRGs。PRGs亚组分析显示了不同的生存结果以及对化疗和免疫检查点阻断疗法的不同反应。发现GPX4和NOD2的高表达，以及CASP6、PRKACA和NLRP2的低水平与较高的总生存率（OS）显著相关（p < 0.05）。相反，NOD2的低表达与无进展生存期较低（p = 0.021）和肿瘤晚期（p = 0.0024）相关。NOD2、NLRP2和TNM分期被确定为独立的预后因素（p < 0.001）。LASSO预后模型显示高危评分组的EC患者OS显著降低（ROC-AUC：0.799，p = 0.00644）。此外，NOD2与免疫细胞浸润和免疫检查点表达呈正相关（p < 0.001）。GPX4和CASP6与肿瘤突变负荷（TMB）和微卫星不稳定性（MSI）显著相关（R = 0.39；R = 0.23）。此外，在EC细胞和组织中均证实NOD2显著上调，表明晚期TNM分期（p < 0.0001）与M1表型巨噬细胞浸润之间存在正相关。尽管如此，其对患者OS的影响未达到统计学意义（p = 0.141）。我们的研究结果有助于推进EC患者的预后模型。NOD2受体介导的细胞焦亡机制可能调节肿瘤免疫，并促进巨噬细胞从M2表型向M1表型的转变，这对EC的进展有显著影响。
