Gan Wenqiang, Wang Weiqi, Li Tiegang, Zhang Rixin, Hou Yufang, Lv Silin, Zeng Zifan, Yan Zheng, Yang Min
State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
J Cancer. 2022 Mar 6;13(5):1588-1602. doi: 10.7150/jca.66949. eCollection 2022.
Cohesin is a highly conserved and ubiquitously expressed protein complex. While increasing evidence suggests that cohesin dysregulation is vital in the carcinogenesis of numerous malignancies, little is known about the prognostic values and potential mechanisms of cohesin subunits and direct regulators in esophageal carcinoma (ESCA). RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) were used. The subunits and regulators of cohesin affecting the prognosis of ESCA were screened by Kaplan-Meier survival analysis; univariate and multivariate Cox regression analyses were performed; and the receiver-operating characteristic (ROC) curve was determined. The ESCA hazard model and nomogram map were constructed by integrating the clinical data. We used functional analysis and protein-protein interaction (PPI) networks to explore underlying pathways. Finally, immunohistochemistry was performed to examine the expression levels of cohesin subunits in tissue microarray (TMA). Transcriptome data from multiple ESCA patient datasets showed cohesin subunits SMC1A, SMC1B, SMC3, STAG1, STAG2, RAD21, and cohesin regulators including ESCO2, NIPBL, MAU2, WAPL, PDS5A and PDS5B were all upregulated in ESCA tissues compared to normal tissues. Survival analysis demonstrated that high STAG2 expression was significantly associated with poorer overall survival (OS) and progression-free survival (PFS) in esophageal adenocarcinoma (EAC). In contrast, high RAD21 expression was significantly correlated with better OS in esophageal squamous cell carcinoma (ESCC). Moreover, STAG2 and RAD21 were identified as independent prognostic factors and predictive biomarkers in EAC and ESCC, respectively. Functional enrichment analysis further revealed that STAG2 and RAD21 were mainly involved in the mitotic nuclear division, DNA repair, angiogenesis, epithelial-mesenchymal transition (EMT), and oncogenic signaling pathways. PPI analysis illustrated that STAG2 and RAD21 could cross-talk through cancer-associated modules and performed the core roles of the whole PPI network. Using TMA, STAG2 protein expression positively correlated with lymph node metastasis and advanced clinical stage of EAC patients, whereas there was a negative correlation between RAD21 protein expression and the malignant clinicopathological parameters in ESCC. These findings suggest that STAG2 and RAD21 can be used as predictive biomarkers for risk assessment and prognostic stratification in ESCA, which provide potential novel insights into molecular targets of ESCA.
黏连蛋白是一种高度保守且广泛表达的蛋白质复合物。尽管越来越多的证据表明黏连蛋白失调在众多恶性肿瘤的致癌过程中至关重要，但关于黏连蛋白亚基和直接调节因子在食管癌（ESCA）中的预后价值和潜在机制却知之甚少。使用了来自癌症基因组图谱（TCGA）和基因组组织表达（GTEx）的RNA测序数据。通过Kaplan-Meier生存分析筛选影响ESCA预后的黏连蛋白亚基和调节因子；进行单变量和多变量Cox回归分析；并确定受试者操作特征（ROC）曲线。通过整合临床数据构建ESCA风险模型和列线图。我们使用功能分析和蛋白质-蛋白质相互作用（PPI）网络来探索潜在途径。最后，进行免疫组织化学检测组织微阵列（TMA）中黏连蛋白亚基的表达水平。来自多个ESCA患者数据集的转录组数据显示，与正常组织相比，ESCA组织中黏连蛋白亚基SMC1A、SMC1B、SMC3、STAG1、STAG2、RAD21以及黏连蛋白调节因子包括ESCO2、NIPBL、MAU2、WAPL、PDS5A和PDS5B均上调。生存分析表明，高STAG2表达与食管腺癌（EAC）患者较差的总生存期（OS）和无进展生存期（PFS）显著相关。相反，高RAD21表达与食管鳞状细胞癌（ESCC）患者较好的OS显著相关。此外，STAG2和RAD21分别被确定为EAC和ESCC中的独立预后因素和预测生物标志物。功能富集分析进一步揭示，STAG2和RAD21主要参与有丝分裂核分裂、DNA修复、血管生成、上皮-间质转化（EMT）和致癌信号通路。PPI分析表明，STAG2和RAD21可通过癌症相关模块相互作用，并在整个PPI网络中发挥核心作用。使用TMA，STAG2蛋白表达与EAC患者的淋巴结转移和临床晚期呈正相关，而RAD21蛋白表达与ESCC患者的恶性临床病理参数呈负相关。这些发现表明，STAG2和RAD21可作为ESCA风险评估和预后分层的预测生物标志物，为ESCA的分子靶点提供了潜在的新见解。
