Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
School of Public Health, University of South China, Hengyang, China.
Environ Toxicol. 2024 Jun;39(6):3548-3562. doi: 10.1002/tox.24197. Epub 2024 Mar 13.
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.
肿瘤细胞转移是鼻咽癌（NPC）患者死亡的主要原因。miR-2110 在 EBV 阳性 NPC 中被克隆和鉴定，但在 NPC 中的作用尚不清楚。在这项研究中，我们研究了 miR-2110 对 NPC 转移的影响及其相关的分子基础。此外，我们还探讨了 miR-2110 是否可以被华蟾素（CB）调控，并参与 CB 对 NPC 转移的抑制作用。生物信息学、RT-PCR 和原位杂交用于观察 miR-2110 在 NPC 组织和细胞中的表达。划痕、Boyden 和尾静脉转移裸鼠模型用于检测 miR-2110 对 NPC 转移的影响。Western blot、Co-IP、荧光素酶活性、共聚焦显微镜和泛素化测定的细胞共定位用于鉴定 miR-2110 影响 NPC 转移的分子机制。最后，探讨了 CB 诱导的 miR-2110 参与 CB 刺激抑制 NPC 转移的作用。结果表明，miR-2110 的增加显著抑制 NPC 细胞的迁移、侵袭和转移。抑制 miR-2110 显著恢复了 NPC 细胞的迁移和侵袭。机制上，miR-2110 直接靶向 FGFR1 并降低其蛋白表达。FGFR1 的减少减弱了其对 NEDD4 的募集，从而降低了 NEDD4 诱导的磷酸酶和张力蛋白同源物（PTEN）泛素化和降解，并进一步增加了 PTEN 蛋白的稳定性，从而使 PI3K/AKT 刺激的上皮-间充质转化信号失活，并最终抑制 NPC 转移。有趣的是，华蟾素（CB），一种 NPC 转移的潜在新抑制剂，通过抑制 PI3K/AKT/c-Jun 介导的转录抑制，显著诱导 miR-2110 的表达。抑制 miR-2110 显著恢复了 CB 处理的 NPC 细胞的迁移和侵袭。最后，临床样本分析表明，miR-2110 的减少与 NPC 淋巴结转移呈负相关，与 NPC 患者的生存预后呈正相关。总之，miR-2110 是一种转移抑制因子，涉及 CB 诱导的 NPC 转移抑制。
