Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by its aggressive clinical behavior and intricate microenvironment regulation, leading to dismal prognosis. Elucidating the molecular mechanisms underlying PDAC pathogenesis is crucial for developing improved therapeutic approaches. The functional significance and molecular basis of transcobalamin 1 (TCN1) in PDAC remain largely unexplored. Methods and Results: Through integrated analysis of TCGA and GTEx datasets combined with 80 clinical specimens, we identified significant TCN1 overexpression in PDAC, showing a positive association with tumor stage and negative associations with histological differentiation and overall survival. Functional investigations showed that TCN1 enhanced pancreatic cancer cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in both in vitro and in vivo models. Mechanistically, TCN1 physically interacts with signal transducer and activator of transcription 4 (STAT4) to enhance its transcriptional activity. Chromatin immunoprecipitation (ChIP) assays showed that STAT4-mediated transcriptional activation of dual oxidase 2 (DUOX2) occurs through direct promoter binding. As a pivotal reactive oxygen species (ROS)-generating enzyme, DUOX2 overexpression elevates intracellular ROS levels, thereby promoting EMT progression and activating proliferation-related signaling cascades. Antioxidant treatment effectively abrogated TCN1-driven oncogenic phenotypes, establishing ROS as the critical downstream mediator. Conclusions: Collectively, our findings reveal a novel TCN1/STAT4/DUOX2 regulatory axis that exacerbates PDAC progression by remodeling redox homeostasis. This signaling cascade may serve as a prognostic biomarker and a potential therapeutic target for ROS-directed precision therapy in PDAC.
背景：胰腺导管腺癌（PDAC）以其侵袭性临床行为和复杂的微环境调控为特征，导致预后极差。阐明PDAC发病的分子机制对于开发更有效的治疗方法至关重要。转钴胺素1（TCN1）在PDAC中的功能意义和分子基础在很大程度上仍未得到探索。方法与结果：通过对TCGA和GTEx数据集的整合分析并结合80例临床标本，我们发现TCN1在PDAC中显著过表达，其表达水平与肿瘤分期呈正相关，与组织学分化程度和总生存期呈负相关。功能研究表明，在体外和体内模型中，TCN1均能增强胰腺癌细胞的增殖、迁移、侵袭和上皮-间质转化（EMT）。机制上，TCN1与信号转导和转录激活因子4（STAT4）发生物理相互作用，从而增强其转录活性。染色质免疫沉淀（ChIP）实验表明，STAT4通过直接结合启动子介导了双氧化酶2（DUOX2）的转录激活。作为一种关键的活性氧（ROS）生成酶，DUOX2的过表达提高了细胞内ROS水平，从而促进EMT进程并激活增殖相关的信号级联反应。抗氧化剂处理有效阻断了TCN1驱动的致癌表型，证实ROS是关键的下游介质。结论：总之，我们的研究揭示了一个新的TCN1/STAT4/DUOX2调控轴，该轴通过重塑氧化还原稳态加剧了PDAC的进展。这一信号级联反应可作为PDAC中ROS导向精准治疗的预后生物标志物和潜在治疗靶点。
肿瘤(癌症)患者之家