Fan Xiangyu, Qiao Wenjuan, Guo Xu, Wang Jiaqi, Zhao Lisong
Department of Radiation Oncology, The Fourth Hospital of Harbin Medical University, No. 37, Yiyuan street, Nangang District, Harbin, 150001, Heilongjiang, China.
Sci Rep. 2025 May 23;15(1):17884. doi: 10.1038/s41598-025-02129-1.
m6A modifications are involved in regulating microRNA (miRNA) processing and maturation, and are associated with tumor development. Therefore, this study was aimed to explore the mechanism of miR-122-5p in regulating hepatocellular carcinoma (HCC) progression. mRNA expression and transfection efficiency were detected by RT-qPCR. Western blot was employed to measure protein level. Cell functions were evaluated through CCK-8 and transwell, respectively. Intracellular m6A levels were analyzed by MeRIP. Dual luciferase reporter gene, RIP and co-IP were applied to verify the binding relationship. Xenograft tumor model was carried out for in vivo validation of miR-122-5p function. We reported that miR-122-5p was clearly lessened in HCC. Functionally, miR-122-5p introduction inhibited the malignant progression of HCC. Mechanistically, METTL14 insertion promoted miR-122-5p maturation by labeling pri-miR-122 with m6A. In addition, miR-122-5p exerted suppressor effects by targeting Lysine acetyltransferase 2 A(KAT2A). Moreover, we also found that KAT2A overexpression limited β-catenin expression through succinylation modification. Finally, animal data also illustrated that miR-122-5p introduction could hinder the growth of HCC tumors in vivo. We revealed the existence of a METTL14/miR-122-5p/KAT2A/β-catenin mechanistic axis in HCC, which has not been reported in the literature. This newly discovered mechanistic axis may provide new ideas for HCC therapy.
m6A修饰参与调节微小RNA（miRNA）的加工和成熟，并与肿瘤发展相关。因此，本研究旨在探讨miR-122-5p调节肝细胞癌（HCC）进展的机制。通过RT-qPCR检测mRNA表达和转染效率。采用蛋白质印迹法检测蛋白质水平。分别通过CCK-8和Transwell评估细胞功能。通过MeRIP分析细胞内m6A水平。应用双荧光素酶报告基因、RIP和co-IP验证结合关系。建立异种移植瘤模型对miR-122-5p的功能进行体内验证。我们发现miR-122-5p在HCC中明显降低。在功能上，导入miR-122-5p可抑制HCC的恶性进展。机制上，METTL14插入通过用m6A标记pri-miR-122促进miR-122-5p成熟。此外，miR-122-5p通过靶向赖氨酸乙酰转移酶2A（KAT2A）发挥抑制作用。而且，我们还发现KAT2A过表达通过琥珀酰化修饰限制β-连环蛋白的表达。最后，动物实验数据也表明导入miR-122-5p可在体内抑制HCC肿瘤生长。我们揭示了HCC中存在METTL14/miR-122-5p/KAT2A/β-连环蛋白机制轴，这在文献中尚未见报道。这一新发现的机制轴可能为HCC治疗提供新思路。
