Clinical Medical Research Center, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
Department of Otorhinolaryngology, The First Affiliated Hospital, Hengyang Medical School, University of South China, 421001, Hengyang, Hunan, China.
Cell Death Dis. 2024 Oct 8;15(10):733. doi: 10.1038/s41419-024-07097-4.
Epigenetic reprogramming plays a critical role in cancer progression of cancer, and N6-methyladenosine (m6A) is the most common RNA modification in eukaryotes. The purpose of this study was to explore the related modification mode of m6A regulator construction and evaluate the invasion and migration of thyroid cancer. Our results showed that m6A levels were significantly increased in papillary thyroid cancer (PTC) and anaplastic thyroid cancer (ATC) samples, which may have been induced by the down-regulation of demethylase fat mass and obesity-associated gene (FTO). Moreover, FTO inhibited PTC and ATC invasion and metastasis through the epithelial-to-mesenchymal transition (EMT) pathway in vivo and in vitro. Mechanistically, an m6A-mRNA epitranscriptomic microarray showed that Cadherin 12 (CDH12) is the key target gene mediated by FTO in an m6A-dependent manner. CDH12 promotes invasion and metastasis through the EMT pathway in thyroid cancer, both in vivo and in vitro. Furthermore, we found that insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is an important m6A reading protein, that regulates the stability of CDH12 mRNA and mediates EMT progression, thereby promoting the invasion and metastasis of PTC and ATC. Thus, FTO, IGF2BP2 and CDH12 may be effective therapeutic targets for PTC and ATC with significant invasion or distant metastasis. Schematic summary of FTO-IGF2BP2 axis in modulation of CDH12 mRNA m6A and upregulation of CDH12 expression in the invasion and metastasis of thyroid carcinoma.
表观遗传重编程在癌症进展中起着关键作用，N6-甲基腺苷（m6A）是真核生物中最常见的 RNA 修饰。本研究旨在探讨 m6A 调节因子构建的相关修饰模式，并评估其在甲状腺癌中的侵袭和迁移能力。我们的研究结果表明，m6A 水平在甲状腺乳头状癌（PTC）和间变性甲状腺癌（ATC）样本中显著升高，这可能是由于去甲基化酶脂肪量和肥胖相关基因（FTO）下调所致。此外，FTO 通过体内和体外上皮间质转化（EMT）途径抑制 PTC 和 ATC 的侵袭和转移。在机制上，m6A-mRNA 表转录组微阵列显示 Cadherin 12（CDH12）是 FTO 以 m6A 依赖方式介导的关键靶基因。CDH12 通过 EMT 通路在体内和体外促进甲状腺癌的侵袭和转移。此外，我们发现胰岛素样生长因子 2 mRNA 结合蛋白 2（IGF2BP2）是一种重要的 m6A 阅读蛋白，它调节 CDH12 mRNA 的稳定性并介导 EMT 进展，从而促进 PTC 和 ATC 的侵袭和转移。因此，FTO、IGF2BP2 和 CDH12 可能是具有显著侵袭性或远处转移的 PTC 和 ATC 的有效治疗靶点。FTO-IGF2BP2 轴在调节 CDH12 mRNA m6A 及其在上皮间质转化中的上调中的示意图总结，从而促进甲状腺癌的侵袭和转移。
