ZNF468/AURKA/PI3K/AKT Positive Feedback Loop Promotes Proliferation and Metastasis of Oesophageal Squamous Cell Carcinoma

Abstract

While prior research linked ZNF468 to radioresistance in oesophageal squamous cell carcinoma (ESCC), its broader role in ESCC progression remained unclear. This study elucidates these functions and underlying mechanisms. Immunohistochemistry on clinical ESCC tissues demonstrated ZNF468 upregulation, which correlated with unfavourable patient outcomes and increased Aurora A expression. In vitro experiments, including assessments of proliferation, apoptosis, migration and invasion, revealed that ZNF468 overexpression enhanced these oncogenic phenotypes in ESCC cells, while its knockdown produced inhibitory effects. These findings were corroborated in vivo using subcutaneous tumour and lung metastasis models. Mechanistically, ZNF468 was found to upregulate AURKA expression, subsequently activating the PI3K/AKT signalling pathway, thereby promoting cell proliferation and epithelial-mesenchymal transition (EMT). Importantly, pharmacological inhibition of AURKA or the PI3K/AKT pathway significantly attenuated the pro-tumorigenic effects driven by ZNF468. Furthermore, AKT was shown to augment ZNF468 protein stability and transcriptional activity, establishing a ZNF468/AURKA/PI3K/AKT positive feedback loop. In conclusion, this study identifies a critical positive feedback mechanism involving ZNF468/AURKA/PI3K/AKT that significantly promotes ESCC progression, underscoring ZNF468 as a potential therapeutic target.