State Key Lab of Respiratory Disease, Institute for Chemical Carcinogenesis, Collaborative Innovation Center for Environmental Toxicity, School of Public Health, Guangzhou Medical University, 1 Xinzao Road, Xinzao, Panyu District, Guangzhou, 511436, China.
Department of Obstetrics and Gynecology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
BMC Cancer. 2023 Sep 18;23(1):879. doi: 10.1186/s12885-023-11358-4.
The epithelial-mesenchymal transition (EMT) plays an indispensable role in the development and progression of Endometrial cancer (EC). Nevertheless, little evidence is reported to uncover the functionality and application of EMT-related molecules in the prognosis of EC. This study aims to develop novel molecular markers for prognosis prediction in patients with EC.
RNA sequencing profiles of EC patients obtained from The Cancer Genome Atlas (TCGA) database were used to screen differential expression genes (DEGs) between tumors and normal tissues. The Cox regression model with the LASSO method was utilized to identify survival-related DEGs and to establish a prognostic signature whose performance was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC) and calibration curve. Eventually, functional enrichment analysis and cellular experiments were performed to reveal the roles of prognosis-related genes in EC progression.
A total of 540 EMT-related DEGs in EC were screened, and subsequently a four-gene risk signature comprising SIRT2, SIX1, CDKN2A and PGR was established to predict overall survival of EC. This risk signature could serve as a meaningfully independent indicator for EC prognosis via multivariate Cox regression (HR = 2.002, 95%CI = 1.433-2.798; P < 0.001). The nomogram integrating the risk signature and clinical characteristics exhibited robust validity and performance at predicting EC overall survival indicated by ROC and calibration curve. Functional enrichment analysis revealed that the EMT-related genes risk signature was associated with extracellular matrix organization, mesenchymal development and cellular component morphogenesis, suggesting its possible relevance to epithelial-mesenchymal transition and cancer progression. Functionally, we demonstrated that the silencing of SIX1, SIRT2 and CDKN2A expression could accelerate the migratory and invasive capacities of tumor cells, whereas the downregulation of PGR dramatically inhibited cancer cells migration and invasion.
Altogether, a novel four-EMT-related genes signature was a potential biomarker for EC prognosis. These findings might help to ameliorate the individualized prognostication and therapeutic treatment of EC patients.
上皮-间充质转化（EMT）在子宫内膜癌（EC）的发生和发展中起着不可或缺的作用。然而，很少有证据表明 EMT 相关分子在 EC 的预后中的功能和应用。本研究旨在为 EC 患者的预后预测开发新的分子标志物。
从癌症基因组图谱（TCGA）数据库中筛选出 EC 患者的 RNA 测序图谱，以筛选肿瘤与正常组织之间的差异表达基因（DEGs）。采用 Cox 回归模型和 LASSO 方法筛选出与生存相关的 DEGs，并建立一个预后标志物，通过 Kaplan-Meier 曲线、受试者工作特征（ROC）和校准曲线评估其性能。最后，进行功能富集分析和细胞实验，揭示与 EC 进展相关的预后相关基因的作用。
筛选出 EC 中共有 540 个 EMT 相关的 DEGs，随后建立了一个由 SIRT2、SIX1、CDKN2A 和 PGR 组成的四基因风险标志物，用于预测 EC 的总生存率。该风险标志物可以通过多变量 Cox 回归（HR=2.002，95%CI=1.433-2.798；P<0.001）作为 EC 预后的一个有意义的独立指标。包含风险标志物和临床特征的列线图在预测 EC 总生存率方面表现出强大的准确性和性能，ROC 和校准曲线也证实了这一点。功能富集分析表明，EMT 相关基因风险标志物与细胞外基质组织、间充质发育和细胞成分形态发生有关，提示其可能与上皮-间充质转化和癌症进展有关。功能上，我们证明了沉默 SIX1、SIRT2 和 CDKN2A 的表达可以加速肿瘤细胞的迁移和侵袭能力，而下调 PGR 则显著抑制了癌细胞的迁移和侵袭。
总之，一个新的 EMT 相关的四个基因的标志物是 EC 预后的一个潜在的生物标志物。这些发现可能有助于改善 EC 患者的个体化预后预测和治疗治疗。
