Targeting Drp1 inhibits ESCC progression via the ROS-PGC1-α-Nrf1/2 pathway.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.