Liang Lunxi, Liang Xiao, Yu Xueke, Xiang Wanting
Department of Gastroenterology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, China.
Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, China.
J Cancer. 2024 Aug 19;15(16):5376-5395. doi: 10.7150/jca.98723. eCollection 2024.
Colorectal cancer is the third most common cause of cancer death worldwide. We probed the correlations between E3 ubiquitin ligase (E3)-related genes (ERGs) and colon cancer prognosis and immune responses. Gene expression profiles and clinical data of patients with colon cancer were acquired from the TCGA, GTEx, GSE17537 and GSE29621 databases. ERGs were identified by coexpression analysis. WGCNA and differential expression analysis were subsequently conducted. Consensus clustering identified two molecular clusters. Differential analysis of the two clusters and Cox regression were then conducted. A prognostic model was constructed based on 10 machine learning algorithms and 92 algorithm combinations. The CIBERSORT, ssGSEA and TIMER algorithms were used to estimate immune infiltration. The OncoPredict algorithm and The Cancer Immunome Atlas (TCIA) predicted susceptibility to chemotherapeutic and targeted drugs and immunotherapy sensitivity. CCK-8, scratch-wound and RT‒PCR assays were subsequently conducted. Two ERG-associated clusters were identified. The prognosis and immune function of patients in cluster A were superior to those of patients in cluster B. We constructed a prognostic model with perfect predictive capability and validated it in internal and external colon cancer datasets. We discovered significant discrepancies in immune infiltration and immune checkpoints between different risk groups. The group with high-risk had a reduced half-maximal inhibitory concentration (IC50) for some routine antitumor drugs and reduced susceptibility to immunotherapy. experiments demonstrated that the ectopic expression of PRELP inhibited the migration and proliferation of CRC cells. In summary, we identified novel molecular subtypes and developed a prognostic model, which will help a lot in the advancement of better forecasting and therapeutic approaches.
结直肠癌是全球第三大常见癌症死因。我们探究了E3泛素连接酶（E3）相关基因（ERGs）与结肠癌预后及免疫反应之间的相关性。从TCGA、GTEx、GSE17537和GSE29621数据库获取了结肠癌患者的基因表达谱和临床数据。通过共表达分析鉴定ERGs。随后进行加权基因共表达网络分析（WGCNA）和差异表达分析。共识聚类确定了两个分子簇。然后对这两个簇进行差异分析和Cox回归。基于10种机器学习算法和92种算法组合构建了一个预后模型。使用CIBERSORT、单样本基因集富集分析（ssGSEA）和肿瘤免疫估计资源（TIMER）算法来估计免疫浸润。OncoPredict算法和癌症免疫图谱（TCIA）预测对化疗和靶向药物的敏感性以及免疫治疗敏感性。随后进行细胞计数试剂盒-8（CCK-8）、划痕试验和逆转录-聚合酶链反应（RT-PCR）检测。鉴定出两个与ERG相关的簇。A簇患者的预后和免疫功能优于B簇患者。我们构建了一个具有完美预测能力的预后模型，并在内部和外部结肠癌数据集中对其进行了验证。我们发现不同风险组之间在免疫浸润和免疫检查点方面存在显著差异。高风险组对一些常规抗肿瘤药物的半数最大抑制浓度（IC50）降低，对免疫治疗的敏感性降低。实验表明，富含脯氨酸的表皮蛋白（PRELP）的异位表达抑制了结直肠癌细胞的迁移和增殖。总之，我们鉴定了新的分子亚型并开发了一个预后模型，这将有助于更好地推进预测和治疗方法。
