Bufalin targeting METTL17 inhibits the occurrence and metastasis of oral cancer through JAK1/STAT3 signaling pathway.

Oral cancer (OC) is a malignant tumor that arises at the mucosal tissues of the oral cavity and is commonly treated with surgical resection. Bufalin is one of the most potent anticancer monomers extracted from bufonis venenum and has been shown to have anticancer effects against a wide range of cancers, including lung cancer, gastric cancer and hepatocellular carcinomas. However, there are fewer studies on the role of bufalin in OC and a lack of clear targets. Moreover, bufalin is more difficult to apply clinically due to its cardiac glycoside effects. Notably, oral cancer is a facial tumor, and bufalin acts first in the oral tissues and does not need to go through the blood circulation to reach the heart, which greatly mitigates the risk and overcomes the major limitation. The effects of bufalin on the proliferation and migration of oral cancer cells were detected by CCK-8 assay, wound healing assay, transwell assay and Western blot. Potential direct interacting proteins of bufalin were screened by human proteomic microarray, and the binding sites were predicted using molecular docking technology. In vitro and vivo biological experiments were performed to verify the role of bufalin direct interacting protein and the mechanism by which bufalin targets this protein to inhibit OC metastasis. The results showed that bufalin inhibited the proliferation and migration of OC cell lines from Cal-27, HN30 and SCC-15 cultured in vitro. METTL17, a direct-interacting protein of bufalin, has several potential binding sites with bufalin. METTL17 is highly expressed in OC and promotes OC occurrence and development in vitro and vivo through activation of the JAK1/STAT3 signaling pathway. Bufalin reversed the promotional effect of METTL17 on OC by down-regulating METTL17 expression. These results provide a new rationale for bufalin as a promising drug for the treatment of OC and avoid the difficulty that bufalin has a strong cardiac glycosides effect on the heart through the bloodstream.