Abstract
Objective:
Esophageal squamous cell carcinoma (ESCC) is a lethal malignancy with limited therapeutic options, primarily due to its aggressive metastatic behavior. This study aimed to elucidate the molecular drivers of ESCC metastasis by identifying a critical oncogene and investigate its functional mechanisms.
Methods:
Using integrated bioinformatics screening, we identified NDC80 as a potential regulator of metastasis. The role and underlying mechanisms of NDC80 in ESCC progression have remained to be fully elucidated. We conducted in vitro functional assays-including real-time PCR, western blotting, and flow cytometry-to assess the effects of NDC80 on epithelial-mesenchymal transition (EMT) and malignant behavior. Mechanistic studies such as co-culture systems and ELISA, were used to evaluate tumor-associated macrophages (TAMs) polarization, with a specific focus on the PI3K/AKT pathway. In vivo, we established subcutaneous xenograft models in immunocompromised mice to validate the impact of NDC80 on ESCC progression. Clinical validation was performed using immunohistochemistry analysis of ESCC tissue samples.
Results:
NDC80 was identified as a clinically significant oncogene, showing marked overexpression in ESCC tissues that was associated with advanced invasion depth, lymphatic metastasis, and vascular invasion. Functionally, NDC80 promoted tumor cell migration, invasion, and EMT progression. Mechanistically, NDC80 fostered a tumor-promoting microenvironment by inducing M2 macrophages polarization via secretion of M-CSF and CXCL-2, which in turn activated the PI3K/AKT pathway to further amplify EMT.
Conclusion:
Our findings established NDC80 as a master regulator of ESCC metastasis by activating TAM-mediated PI3K/AKT and promoting EMT. These insights positioned NDC80 as a promising therapeutic target, offering a potential strategy to prevent ESCC progression.
Keywords:
Epithelial-mesenchymal transition; Esophageal squamous cell carcinoma; NDC80; PI3K/AKT; Tumor-associated macrophages.