Jiang Zhixiong, Yang Yating, Zhou Jinchi, Li Xin, Meng Qingqing, Yu Xiangyi, Xue Yaxin, Li Mengyu, Cai Yichen, Han Pengchun, Jiang Mingjun, Wang Huizhen, Liu Congrong, Zhao Jing, Wan Lixin, Bao Dengke
Laboratory of Cancer Biomarkers and Liquid Biopsy, School of Pharmacy, Henan University, Kaifeng, 475000, Henan, China.
The Zhongzhou Laboratory for Integrative Biology, Henan University, Zhengzhou, 450000, Henan, China.
J Transl Med. 2025 Jun 17;23(1):674. doi: 10.1186/s12967-025-06697-8.
Esophageal squamous cell carcinoma (ESCC) ranks among the most prevalent malignancies of the digestive tract. Due to the absence of obvious symptoms in patients with early-stage ESCC, most cases are diagnosed at advanced stages, highlighting the urgent need to investigate the specific mechanisms underlying ESCC progression. Mitochondrial dysfunction plays a pivotal role in tumor progression by regulating multiple biological processes. Dynamin-related protein 1 (Drp1), which is involved in the regulation of mitochondrial fission, is closely associated with tumor progression. However, its role in the metastasis of ESCC remains to be fully elucidated.
This study utilized database analysis and immunohistochemistry to evaluate the expression of Drp1 in ESCC tissues. Functional cell experiments and mouse models were performed to elucidate the mechanisms by which Drp1 influences ESCC cell growth and metastasis. Furthermore, the TargetScan online platform was employed to predict microRNAs that may interact with Drp1 to further explore the specific mechanism of Drp1 on the progression of ESCC.
We found that high expression of Drp1 was correlated with poor prognosis of ESCC patients. Furthermore, Drp1 overexpression significantly enhanced the growth and metastasis of ESCC cell both in vitro and in vivo. Mechanistically, we showed that Drp1 overexpression activated the PGC1-α-Nrf1/2 signaling and promoted the process of epithelial-mesenchymal transition (EMT) in ESCC cells, thereby facilitating tumor cell metastasis. Additionally, miR-203a-3p targeted and down-regulated Drp1 expression in ESCC cells, effectively inhibiting Drp1-mediated metastasis through the ROS-PGC1-α-Nrf1/2 pathway.
These findings uncover that Drp1 overexpression drived the growth and metastasis of ESCC via ROS-PGC1-α-Nrf1/2 signaling pathway, while miR-203a-3p significantly inhibited Drp1 expression and its capacity to mediate the malignant progression of ESCC cells. Our results provide potential novel therapeutic targets for the treatment of ESCC.
食管鳞状细胞癌（ESCC）是消化道最常见的恶性肿瘤之一。由于早期ESCC患者没有明显症状，大多数病例在晚期才被诊断出来，这凸显了迫切需要研究ESCC进展的具体机制。线粒体功能障碍通过调节多种生物学过程在肿瘤进展中起关键作用。参与线粒体分裂调节的动力相关蛋白1（Drp1）与肿瘤进展密切相关。然而，其在ESCC转移中的作用仍有待充分阐明。
本研究利用数据库分析和免疫组织化学评估Drp1在ESCC组织中的表达。进行功能细胞实验和小鼠模型以阐明Drp1影响ESCC细胞生长和转移的机制。此外，利用TargetScan在线平台预测可能与Drp1相互作用的微小RNA，以进一步探索Drp1在ESCC进展中的具体机制。
我们发现Drp1高表达与ESCC患者的不良预后相关。此外，Drp1过表达在体外和体内均显著增强了ESCC细胞的生长和转移。机制上，我们表明Drp1过表达激活了PGC1-α-Nrf1/2信号通路，并促进了ESCC细胞中的上皮-间质转化（EMT）过程，从而促进肿瘤细胞转移。此外，miR-203a-3p靶向并下调ESCC细胞中Drp1的表达，通过ROS-PGC1-α-Nrf1/2途径有效抑制Drp1介导的转移。
这些发现揭示了Drp1过表达通过ROS-PGC1-α-Nrf1/2信号通路驱动ESCC的生长和转移，而miR-203a-3p显著抑制Drp1表达及其介导ESCC细胞恶性进展的能力。我们的结果为ESCC的治疗提供了潜在的新型治疗靶点。
