MiR-2110 induced by chemically synthesized cinobufagin functions as a tumor-metastatic suppressor via targeting FGFR1 to reduce PTEN ubiquitination degradation in nasopharyngeal carcinoma

Abstract

Abstract Tumor cell metastasis is the key cause of death in patients with nasopharyngeal carcinoma(NPC). MiR-2110 was cloned and identified in Epstein-Barr virus (EBV)-positive NPC, but its role is unclear in NPC. In this study, we investigated the effect of miR-2110 on NPC metastasis and its related molecular basis. In addition, we also explored whether miR-2110 can be regulated by Cinobufotalin(CB) and participate in the inhibition of CB on NPC metastasis. Bioinformatics, RT-PCR, and In situ hybridization were used to observe the expression of miR-2110 in NPC tissues and cells. Scratch, boyden and tail vein metastasis model of nude mouse were used to detect the effect of miR-2110 on NPC metastasis. Western blot, CoIP, luciferase activity, co-localization of micro confocal and ubiquitination assays were used to identify the molecular mechanism of miR-2110 affecting NPC metastasis. Finally, miR-2110 induced by CB participates in CB-stimulated inhibition of NPC metastasis was explored. Increased miR-2110 significantly suppressed NPC cell migration, invasion, and metastasis. Suppressing miR-2110 markedly restored NPC cell migration and invasion. Mechanistically, miR-2110 directly targeted FGFR1 and reduced its protein expression. Decreased FGFR1 attenuated its recruitment of NEDD4, which downregulated NEDD4-induced PTEN ubiquitination degradation and increased PTEN protein stability, thereby inactivating PI3K/AKT-stimulated EMT signaling and ultimately suppressing NPC metastasis. Interestingly, cinobufagin (CB), a potential new inhibitory drug for NPC metastasis, significantly induced miR-2110 expression by suppressing PI3K/AKT/c-Jun-mediated transcription inhibition. Suppression of miR-2110 significantly restored cell migration and invasion in CB-treated NPC cells. Finally, a clinical sample assay indicated that reduced miR-2110 was negatively correlated with NPC lymph node metastasis and positively related to NPC patient survival. In summary, miR-2110 is a metastatic suppressor that is involved in CB-induced suppression of NPC metastasis.