Qin Tian Xu, Zhu Ying Ying, Ng Wai Hoe, Ng Siew Kit, Chek Min Fey, Tang Kai Dun
Nankai University, TEDA School of Biological Sciences and Biotechnology, Tianjin, 300457, PR China; Nankai University, Nankai International Advanced Research Institute (Shenzhen Futian), Shenzhen, Guangdong, 518045, PR China.
Queen's University Belfast, School of Medicine, Dentistry and Biomedical Sciences, Belfast, BT7 1NN, UK.
Cancer Lett. 2025 Sep 28;628:217848. doi: 10.1016/j.canlet.2025.217848. Epub 2025 Jun 6.
There is convincing evidence that being overweight or having obesity is associated with an increased risk of developing oral squamous cell carcinoma (OSCC). Despite OSCC frequently spread to the cervical lymph nodes, where adipose tissue is the predominant tissue within the microenvironment, it is still largely unknown whether adipocytes could contribute to the formation of oral cancer stem cells (CSCs) niche during the oral carcinogenesis. Here, we report that adipocytes promote the CSCs phenotype of OSCC cells through the activation of complement C3 (C3). Subsequent clinical data analysis revealed that the elevated levels of C3 and its receptor C3AR are associated with aggressive features and shorter survival in human OSCC patients. Furthermore, C3 exists as an autocrine factor and through C3AR interaction regulates OSCC stemness and properties such as cell proliferation, migration and invasion. On the other hand, C3 and C3AR were found to be highly abundant in adipocytes upon co-cultured with OSCC cells, demonstrating its paracrine effect on adipocyte-CSCs interaction, which in turn promotes CSC properties and supports oral carcinogenesis. Intriguingly, the inhibition of functional C3/C3AR axis by sphingosine, a bioactive sphingolipid metabolite, resulted in the suppression of OSCC cells growth and adipocyte-promoted oral CSC self-renewal. In conclusion, our findings provide a novel insight into the mechanisms underlying the role of C3/C3AR axis in mediating the reciprocal interactions between adipocytes and OSCC cells, acting in an autocrine and paracrine manner, and specific inhibition of this interaction by sphingosine offers a potential targeted therapeutic approach for OSCC treatment.
有令人信服的证据表明，超重或肥胖与患口腔鳞状细胞癌（OSCC）的风险增加有关。尽管OSCC经常扩散到颈部淋巴结，脂肪组织是微环境中的主要组织，但在口腔癌发生过程中，脂肪细胞是否有助于口腔癌干细胞（CSCs）生态位的形成仍不清楚。在此，我们报告脂肪细胞通过激活补体C3（C3）促进OSCC细胞的CSCs表型。随后的临床数据分析显示，C3及其受体C3AR水平升高与人类OSCC患者的侵袭性特征和较短生存期相关。此外，C3作为一种自分泌因子，通过与C3AR相互作用调节OSCC的干性以及细胞增殖、迁移和侵袭等特性。另一方面，在与OSCC细胞共培养时，发现C3和C3AR在脂肪细胞中高度丰富，表明其对脂肪细胞-CSCs相互作用具有旁分泌作用，进而促进CSCs特性并支持口腔癌发生。有趣的是，生物活性鞘脂代谢物鞘氨醇对功能性C3/C3AR轴的抑制导致OSCC细胞生长受抑以及脂肪细胞促进的口腔CSC自我更新受抑。总之，我们的研究结果为C3/C3AR轴在介导脂肪细胞与OSCC细胞之间相互作用的机制提供了新的见解，这种相互作用以自分泌和旁分泌方式起作用，鞘氨醇对这种相互作用的特异性抑制为OSCC治疗提供了一种潜在的靶向治疗方法。
