Li Xiaoxu, Lu Juntao, Zhao Yan, Guo Wei
Department of Radiation Oncology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Laboratory of Pathology, Hebei Cancer Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
J Cancer. 2025 Mar 21;16(7):2103-2123. doi: 10.7150/jca.104376. eCollection 2025.
Increasing evidence highlights the critical roles of oxidative stress and endoplasmic reticulum (ER) stress in tumor initiation and progression. However, the specific functions of related genes in esophageal cancer (ESCA) remain poorly understood. To investigate the impact of oxidative and ER stress on ESCA, this study analyzed the TCGA and GEO databases to identify 12 oxidative stress- and ER stress-related differentially expressed genes (OERDEGs). Pathway analysis revealed significant enrichment in critical processes such as PRC2-mediated methylation, oxidative stress-induced senescence, and NOTCH signaling. A novel LASSO regression model was developed to link gene expression with clinical prognosis, and the model was validated through ROC and Cox regression analyses. Four OERDEGs (CDKN3, PINK1, SPP1, and TFRC) were identified as key biomarkers for ESCA prognosis. Notably, TFRC expression was significantly upregulated in ESCA cells under both oxidative and ER stress conditions, in a dose- and time-dependent manner. Functional assays confirmed that TFRC promotes cell proliferation, migration, and invasion by regulating the HIF-1α and NOTCH1 signaling pathways. This study elucidates the complex interplay between oxidative/ER stress and ESCA progression and highlights the innovative application of bioinformatics to identify potential biomarkers for early diagnosis and therapeutic strategies. Targeting TFRC, in particular, may offer a novel approach to improving ESCA treatment and enhancing patient prognosis.
越来越多的证据凸显了氧化应激和内质网（ER）应激在肿瘤发生和发展中的关键作用。然而，相关基因在食管癌（ESCA）中的具体功能仍知之甚少。为了研究氧化应激和内质网应激对食管癌的影响，本研究分析了TCGA和GEO数据库，以鉴定12个氧化应激和内质网应激相关的差异表达基因（OERDEGs）。通路分析显示，在PRC2介导的甲基化、氧化应激诱导的衰老和NOTCH信号传导等关键过程中存在显著富集。开发了一种新的LASSO回归模型，将基因表达与临床预后联系起来，并通过ROC和Cox回归分析对该模型进行了验证。四个OERDEGs（CDKN3、PINK1、SPP1和TFRC）被确定为食管癌预后的关键生物标志物。值得注意的是，在氧化应激和内质网应激条件下，ESCA细胞中TFRC的表达均以剂量和时间依赖性方式显著上调。功能试验证实，TFRC通过调节HIF-1α和NOTCH1信号通路促进细胞增殖、迁移和侵袭。本研究阐明了氧化/内质网应激与食管癌进展之间的复杂相互作用，并突出了生物信息学在识别早期诊断和治疗策略潜在生物标志物方面的创新应用。特别是靶向TFRC可能为改善食管癌治疗和提高患者预后提供一种新方法。
