Zhang Shuaiyuan, Liu Xiaoyong, Zhang Jiaqiang, Chen Kunyi, Li Wei, Yao Yihuan, Wang Anxun, Hou Jinsong
Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Lingyuan Road West, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510080, China; Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, 56 Lingyuan Road West, Guangzhou 510055, China; Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510080, China.
Cell Signal. 2025 Apr;128:111631. doi: 10.1016/j.cellsig.2025.111631. Epub 2025 Jan 28.
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.
铜死亡是一种新发现的非凋亡性细胞死亡形式。癌症相关成纤维细胞（CAFs）可分泌包括外泌体在内的多种生物活性物质，以促进肿瘤进展。然而，CAFs对口腔鳞状细胞癌（OSCC）中铜代谢和铜死亡调节的影响尚未得到研究。在本研究中，我们发现ATP7A表达上调与OSCC中铜含量降低、临床病理特征进展及预后不良相关。敲低ATP7A可显著增加体外铜死亡并抑制恶性进展，同时在体内减少肿瘤生长和转移。此外，共培养实验和双荧光素酶报告基因实验表明，OSCC中ATP7A表达上调是由于CAF来源的外泌体中miR-148b-3p减少所致。观察到miR-148b-3p下调可显著提高ATP7A表达，抑制体外铜死亡并增加恶性进展。此外，体内研究表明该过程促进肿瘤生长和转移。由于摄取了CAFs中miR-148b-3p缺失的外泌体，OSCC表现出低水平的铜死亡，通过靶向ATP7A导致肿瘤微环境中出现更恶性的表型。我们的实验结果表明，靶向miR-148b-3p/ATP7A轴可能是治疗口腔癌的一种有前景治疗方法。
