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

• Published in: Environmental toxicology Vol. 39; no. 6; pp. 3548 - 3562
• Main Authors: Fang, Shiyi, Peng, Lanzhu, Zhang, Mengmin, Hou, Rentao, Deng, Xing, Li, Xiaoning, Xin, Jianyang, Peng, Lingrong, Liu, Zhihua, Liu, Yiyi, Xie, Yingying, Zhou, Beixian, Fang, Weiyi, Liu, Zhen, Cheng, Chao
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.06.2024; Wiley Subscription Services, Inc
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Bioinformatics; Bufanolides - pharmacology; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Degradation; Epstein-Barr virus; Female; Fibroblast growth factor receptor 1; Gene Expression Regulation, Neoplastic - drug effects; Humans; Hybridization; Lymph; Lymph nodes; Male; Medical prognosis; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐2110; Molecular modelling; Nasopharyngeal carcinoma; Nasopharyngeal Carcinoma - genetics; Nasopharyngeal Carcinoma - metabolism; Nasopharyngeal Carcinoma - pathology; Nasopharyngeal Neoplasms - drug therapy; Nasopharyngeal Neoplasms - genetics; Nasopharyngeal Neoplasms - metabolism; Nasopharyngeal Neoplasms - pathology; Neoplasm Metastasis; Neoplasms; Nucleotide sequence; Phosphatase; Proteins; PTEN; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; PTEN protein; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Throat cancer; tumor metastasis; Tumors; ubiquitin; Ubiquitination; Ubiquitination - drug effects; PTEN; nasopharyngeal carcinoma; tumor metastasis; miR‐2110; ubiquitin
• ISSN: 1520-4081; 1522-7278; 1522-7278
• DOI: 10.1002/tox.24197

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, Co‐IP, luciferase activity, colocalization 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. The data showed that increased miR‐2110 significantly suppresses 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 phosphatase and tensin homolog (PTEN) ubiquitination and degradation and further increased PTEN protein stability, thereby inactivating PI3K/AKT‐stimulated epithelial–mesenchymal transition signaling and ultimately suppressing NPC metastasis. Interestingly, 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 prognosis. In summary, miR‐2110 is a metastatic suppressor involving in CB‐induced suppression of NPC metastasis.