Department of Clinical Laboratory, Fujian Medical University Union Hospital, Fuzhou, China; The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China; Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China.
Exp Cell Res. 2024 Sep 1;442(1):114192. doi: 10.1016/j.yexcr.2024.114192. Epub 2024 Aug 8.
N6-methyladenosine (m6A) alteration is an epigenetic regulator widely involved in the tumorigenicity of hepatocellular carcinoma (HCC). The role of YTH N6-methyladenosine RNA binding protein F3 (YTHDF3), an m6A reader in HCC, requires further investigation. Here, we aim to explore the biological properties of YTHDF3 in HCC and its potential mechanisms. The predictive risk model for HCC was developed by analyzing the expression of genes associated with m6A in HCC using online datasets. WB and qPCR were employed to assess YTHDF3 expression in HCC and its correlation with the disease's clinicopathological characteristics. Both in vitro and in vivo methods were utilized to evaluate the biological effects of YTHDF3 in HCC. The potential targets of YTHDF3 were identified and confirmed using RNA-seq, meRIP-seq, and linear amplification and sequencing of cDNA ends (Lace-seq). We confirmed that YTHDF3 is overexpressed in HCC. Patients with higher YTHDF3 expression had a greater risk of cancer recurrence. In both in vitro and in vivo settings, YTHDF3 boosts the migration and invasion capabilities of HCC cells. Through multi-omics research, we identified YTHDF3's downstream target genes as NKD inhibitors of the WNT signaling pathway 1 (NKD1) and the WNT/β-catenin signaling pathway. With m6A modification, YTHDF3 suppresses the transcription and translation of NKD1. Additionally, NKD1 inhibited tumor growth by blocking the WNT/β-catenin signaling pathway. The investigation found that the oncogene YTHDF3 stimulates the WNT/β-catenin signaling pathway by m6A-dependently suppressing NKD1 expression in HCC cells. Our findings suggest that YTHDF3 regulates hepatocarcinogenesis, providing fresh perspectives on potential biomarkers and therapeutic targets for HCC.
N6-甲基腺苷（m6A）改变是一种广泛参与肝细胞癌（HCC）发生的表观遗传调节剂。YTH N6-甲基腺苷 RNA 结合蛋白 F3（YTHDF3）作为 HCC 中的 m6A 读取器的作用需要进一步研究。在这里，我们旨在探索 YTHDF3 在 HCC 中的生物学特性及其潜在机制。使用在线数据集分析与 HCC 中 m6A 相关的基因表达，开发了 HCC 的预测风险模型。使用 WB 和 qPCR 评估 HCC 中 YTHDF3 的表达及其与疾病临床病理特征的相关性。使用体外和体内方法评估 YTHDF3 在 HCC 中的生物学效应。使用 RNA-seq、meRIP-seq 和 cDNA 末端的线性扩增和测序（Lace-seq）鉴定和验证 YTHDF3 的潜在靶标。我们证实 YTHDF3 在 HCC 中过表达。YTHDF3 表达较高的患者癌症复发风险更高。在体外和体内环境中，YTHDF3 均可增强 HCC 细胞的迁移和侵袭能力。通过多组学研究，我们确定了 YTHDF3 的下游靶基因作为 WNT 信号通路抑制剂的 NKD1 和 WNT/β-连环蛋白信号通路。通过 m6A 修饰，YTHDF3 抑制 NKD1 的转录和翻译。此外，NKD1 通过阻断 WNT/β-连环蛋白信号通路抑制肿瘤生长。研究发现，癌基因 YTHDF3 通过 m6A 依赖性抑制 HCC 细胞中 NKD1 的表达来刺激 WNT/β-连环蛋白信号通路。我们的研究结果表明，YTHDF3 调节肝癌发生，为 HCC 的潜在生物标志物和治疗靶点提供了新的视角。
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