Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, Wuxi, China.
Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, Wuxi, China.
Mol Carcinog. 2024 Nov;63(11):2119-2132. doi: 10.1002/mc.23797. Epub 2024 Jul 26.
Many studies have shown that tumor cells that survive radiotherapy are more likely to metastasize, but the underlying mechanism remains unclear. Here we aimed to identify epithelial-mesenchymal transition (EMT)-related key genes, which associated with prognosis and radiosensitivity in rectal cancer. First, we obtained differentially expressed genes by analyzing the RNA expression profiles of rectal cancer retrieved from The Cancer Genome Atlas database, EMT-related genes, and radiotherapy-related databases, respectively. Then, Lasso and Cox regression analyses were used to establish an EMT-related prognosis model (EMTPM) based on the identified independent protective factor Fibulin5 (FBLN5) and independent risk gene EHMT2. The high-EMTPM group exhibited significantly poorer prognosis. Then, we evaluated the signature in an external clinical validation cohort. Through in vivo experiments, we further demonstrated that EMTPM effectively distinguishes radioresistant from radiosensitive patients with rectal cancer. Moreover, individuals in the high-EMTPM group showed increased expression of immune checkpoints compared to their counterparts. Finally, pan-cancer analysis of the EMTPM model also indicated its potential for predicting the prognosis of lung squamous cell carcinoma and breast cancer patients undergoing radiotherapy. In summary, we established a novel predictive model for rectal cancer prognosis and radioresistance based on FBLN5 and EHMT2 expressions, and suggested that immune microenvironment may be involved in the process of radioresistance. This predictive model could be used to select management strategies for rectal cancer.
许多研究表明，放疗后存活的肿瘤细胞更容易转移，但潜在机制尚不清楚。在这里，我们旨在鉴定与直肠癌预后和放射敏感性相关的上皮-间充质转化（EMT）相关关键基因。首先，我们通过分别分析从癌症基因组图谱数据库中检索到的直肠癌的 RNA 表达谱、EMT 相关基因和放射治疗相关数据库，获得了差异表达基因。然后，使用 Lasso 和 Cox 回归分析，基于鉴定出的独立保护因子 Fibulin5（FBLN5）和独立风险基因 EHMT2，建立了一个 EMT 相关预后模型（EMTPM）。高 EMTPM 组的预后明显较差。然后，我们在外部临床验证队列中评估了该特征。通过体内实验，我们进一步证明了 EMTPM 可有效区分对放射治疗有抗性和无抗性的直肠癌患者。此外，与对照组相比，高 EMTPM 组的免疫检查点表达增加。最后，EMTPM 模型的泛癌症分析也表明其具有预测接受放疗的肺鳞癌和乳腺癌患者预后的潜力。总之，我们基于 FBLN5 和 EHMT2 的表达建立了一种新的预测直肠癌预后和放射抵抗的模型，并表明免疫微环境可能参与放射抵抗过程。该预测模型可用于选择直肠癌的管理策略。
