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微小RNA-4713-3p通过靶向抑制EPHX3激活Wnt/β-连环蛋白信号通路促进鼻咽癌恶性进展的作用

Effect of MicroRNA-4713-3p on Promoting Malignant Progression of Nasopharyngeal Carcinoma via Targeted Inhibition of EPHX3 to Activate Wnt/β-Catenin Signaling Pathway.

作者信息

Hong Qichao, Liu Shuzhou, Zhang Qimeng, Ding Shun, Xing Chengliang, Yan Jingren, Zhang Liuyang, Mu Zhonglin

机构信息

Department of Otorhinolaryngology Head and Neck Surgery, Hainan Affiliated Hospital of Hainan Medical University (Hainan General Hospital), Haikou, Hainan, China.

Department of Otolaryngology, Head and Neck Surgery, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan, China.

出版信息

J Biochem Mol Toxicol. 2025 Sep;39(9):e70450. doi: 10.1002/jbt.70450.

DOI:10.1002/jbt.70450
PMID:40878263
Abstract

Nasopharyngeal carcinoma (NPC) represents a common malignancy in the head-and-neck region, and its development and prognosis can be influenced by multiple factors. Epoxide hydrolase 3 (EPHX3) is an enzyme that perform crucial roles in inflammation and tumors regulation. We aim to discuss the expression pattern and biological function of EPHX3 in NPC. The EPHX3 expression patterns in NPC tissues and cell lines were determined by the qRT-PCR technique. Correlations between EPHX3 expression and the clinical characteristics of NPC patients were subsequently assessed. Afterwards, the mechanism of miR-4713 targeting EPHX3 in NPC was validated either in vitro or in vivo. Gene set enrichment analysis and cell experiments were conducted to prove the impact of the EPHX3-regulated downstream Wnt/β-catenin pathway on the progression of NPC and epithelial-mesenchymal transition (EMT). EPHX3 mRNA expression was significantly downregulated in NPC tissues compared with adjacent normal tissues (p < 0.01). Overexpression of miR-4713-3p markedly enhanced cell proliferation (p < 0.05), migration, and invasion, while dual-luciferase and molecular docking confirmed that EPHX3 is a direct target of miR-4713-3p. Mechanistically, key components of the Wnt/β-catenin pathway, including β-catenin and c-Myc, were significantly upregulated following miR-4713-3p overexpression (p < 0.01), whereas EPHX3 overexpression suppressed these changes and inhibited EMT. In vivo, miR-4713-3p knockdown suppressed tumor growth in xenograft models (p < 0.05). Our study reveals the significance of EPHX3 in the development of NPC and offers a basis for the promise of EPHX3 as a possible therapeutic target.

摘要

鼻咽癌(NPC)是头颈部常见的恶性肿瘤,其发生发展及预后受多种因素影响。环氧水解酶3(EPHX3)是一种在炎症和肿瘤调节中发挥关键作用的酶。我们旨在探讨EPHX3在鼻咽癌中的表达模式及生物学功能。采用qRT-PCR技术检测鼻咽癌组织和细胞系中EPHX3的表达模式。随后评估EPHX3表达与鼻咽癌患者临床特征之间的相关性。之后,在体外和体内验证了miR-4713靶向EPHX3在鼻咽癌中的机制。进行基因集富集分析和细胞实验,以证明EPHX3调控的下游Wnt/β-连环蛋白通路对鼻咽癌进展和上皮-间质转化(EMT)的影响。与相邻正常组织相比,鼻咽癌组织中EPHX3 mRNA表达显著下调(p < 0.01)。miR-4713-3p的过表达显著增强了细胞增殖(p < 0.05)、迁移和侵袭,而双荧光素酶和分子对接证实EPHX3是miR-4713-3p的直接靶点。机制上,miR-4713-3p过表达后,Wnt/β-连环蛋白通路的关键成分,包括β-连环蛋白和c-Myc,显著上调(p < 0.01),而EPHX3过表达抑制了这些变化并抑制了EMT。在体内,miR-4713-3p敲低抑制了异种移植模型中的肿瘤生长(p < 0.05)。我们的研究揭示了EPHX3在鼻咽癌发生发展中的重要性,并为EPHX3作为可能的治疗靶点提供了依据。

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