蟾蜍毒素诱导miR-2110靶击FGFR1抑制鼻咽癌肿瘤干性、增殖和转移

miR-2110 was cloned in nasopharyngeal carcinoma(NPC). However, its action was still undetermined in tumors. In the previous study, we observed that miR-2110 suppressed the malignant phenotypes via inactivating PTEN/PI3K/AKT and its downstream signals including tumor stemness, cell cycle, and EMT. Further, we found that FGFR1 was a potential targeted gene of miR-2110. It can bind to NEDD4 and induce its expression, which increased the ubiquitination of PTEN and stimulated its degradation. Furthermore, Toad venom as an anti-tumor component of Chinese medicine preparations upregulated the miR-2110 expression and decreased FGFR1 expression in NPC. In the futher investigation, we will confirm that Toad venom suppresses PI3K/AKT/c-Jun signal and thus upregulates miR-2110 expression. The latter will directly target FGFR1 to reduce its binding with NEDD4 and downregulate its expression, which thus reduces the ubiquitination of PTEN and suppressed its degradation. Increased PTEN will inactivate PI3K/AKT and its downstream signals including tumor stemness, cell cycle, and EMT and finally block tumor stemness, growth, and metastasis. Our study will not only deeply showed that miR-2110 targets FGFR1 suppressing malignant phenotypes of NPC, but further revealed a new anti-tumor molecular basis of Toad venom.

miR-2110在鼻咽癌（NPC）中克隆，但在肿瘤中的作用尚不明确。我们前期发现miR-2110在NPC中表达下调，并作为抑癌候选基因调控PTEN/PI3K/AKT及下游肿瘤干性、细胞周期和EMT信号抑制NPC恶性表型。进一步我们观察到FGFR1是miR-2110潜在的靶基因，能与NEDD4结合并诱导其表达，导致PTEN泛素化降解。此外，蟾蜍毒素作为抗肿瘤中药成分，在NPC中可诱导miR-2110、下调FGFR1表达。后续研究将明确：蟾蜍毒素在NPC中抑制PI3K/AKT/c-Jun，诱导miR-2110表达，从而抑制FGFR1，降低与NEDD4结合并下调其表达，抑制PTEN泛素化，进而抑制PI3K/AKT及其下游肿瘤干性、细胞周期和EMT信号，最终抑制NPC细胞肿瘤干性、生长和转移。本研究不但揭示miR-2110靶击FGFR1抑制NPC恶性表型，且进一步揭示蟾蜍毒素抗肿瘤的崭新分子机理。

研究背景：miR-2110在鼻咽癌（NPC）中克隆，但在肿瘤中的作用尚不明确。我们前期发现miR-2110在NPC中表达下调，并作为抑癌候选基因调控PTEN/PI3K/AKT及下游EMT信号抑制NPC恶性表型。此外，蟾蜍毒素作为抗肿瘤中药成分，在NPC中可诱导miR-2110、ENKUR、MAP2K4表达，作用机理尚不明确。.主要研究内容：明确蟾蜍毒素在NPC中诱导miR-2110、ENKUR以及MAP2K4表达。明确蟾蜍毒素通过诱导miR-2110抑制NPC细胞侵袭、转移。明确蟾蜍毒素也可以通过诱导ENKUR减少p53泛素化降解，抑制NPC侵袭、转移。此外，明确蟾蜍毒素可通过诱导MAP2K4表达，抑制NPC中由miR-BART22介导的顺铂耐药、肿瘤干性及转移。.重要结果及关键数据：本项目研究发现蟾蜍毒素在鼻咽癌中可通过灭活PI3K/AKT/c-Jun信号转录激活miR-2110、ENKUR以及MAP2K4表达。miR-2110作为肿瘤抑制因子靶向FGFR1，降低了FGFR1对E3泛素连接酶NEDD4的招募，从而减少NEDD4对PTEN的泛素化降解，导致PTEN上调，进而失活PI3K/AKT信号及下游EMT，抑制鼻咽癌侵袭及转移。另外，蟾蜍毒素也可以通过诱导肿瘤抑制基因ENKUR的表达，失活β-catenin/c-Jun/MYH9信号，从而减少UBE3A介导的p53泛素化降解，抑制鼻咽癌转移。除此之外，蟾蜍毒素通过上调MAP2K4抑制MYH9/GSK3β/β-catenin及其下游的肿瘤干性和EMT信号，从而显著抑制鼻咽癌中由miR-BART22介导的顺铂耐药、肿瘤干性及转移。.科学意义：本研究不但揭示了miR-2110靶击FGFR1抑制NPC恶性表型，且进一步揭示蟾蜍毒素抗肿瘤的崭新分子机理。