Cancer-associated fibroblasts promote oral squamous cell carcinoma progression by targeting ATP7A via exosome-mediated paracrine miR-148b-3p.

Cuproptosis is a newly discovered form of non-apoptotic cell death. Cancer-associated fibroblasts (CAFs) can secrete various bioactive substances, including exosomes, to promote tumor progression. However, the impact of CAFs on the regulation of copper metabolism and cuproptosis in oral squamous cell carcinomas (OSCC) has not been investigated. In the present study, we revealed that up-regulated expression of ATP7A was correlated with reduced copper abundance, advanced clinicopathological characteristics and poor prognosis in OSCC. The knockdown of ATP7A significantly increased cuproptosis and inhibited malignant progression in vitro, as well as decreased tumor growth and metastasis in vivo. Furthermore, co-culture assays and dual-luciferase reporter demonstrated that upregulated expression of ATP7A in OSCC was due to a reduction of miR-148b-3p in CAF-derived exosomes. The downregulation of miR-148b-3p was observed to significantly elevate ATP7A expression, inhibit cuproptosis and increase malignant progression in vitro. Additionally, in vivo studies demonstrated that this process promoted tumor growth and metastasis. OSCC exhibit a low level of cuproptosis due to the uptake of miR-148b-3p-depleted exosomes from CAFs, leading to a more malignant phenotype in the tumor microenvironment by targeting ATP7A. The results of our experiments suggest that targeting the miR-148b-3p/ATP7A axis might be a promising therapeutic approach for the treatment of oral cancer.