Department of Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
Mol Ther. 2021 May 5;29(5):1821-1837. doi: 10.1016/j.ymthe.2021.01.019. Epub 2021 Jan 21.
Growing evidence indicates that N6-methyladenosine (mA) is the most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells in vitro and in vivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream mA targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between mA modification and plasticity of the tumor microenvironment.
越来越多的证据表明，N6-甲基腺苷（m6A）是真核细胞中最普遍的 RNA 修饰。然而，METTL3 在甲状腺乳头状癌（PTC）发生和发展中的具体作用仍不清楚。在这里，我们发现 METTL3 的下调与 PTC 中的恶性进展和不良预后相关。一系列的增益和缺失功能研究阐明了 METTL3 对 PTC 细胞在体外和体内生长和转移的调节作用。通过结合 RNA 测序（RNA-seq）和 m6A 免疫沉淀测序（meRIP-seq），我们的机制研究指出 c-Rel 和 RelA 是 METTL3 的下游 m6A 靶标。破坏 METTL3 会引发白细胞介素 8（IL-8）的分泌，而在趋化实验和小鼠模型中，升高的 IL-8 浓度促进了肿瘤相关中性粒细胞（TAN）的募集。IL-8 拮抗剂 SB225002 的给药大大减缓了肿瘤的生长，并在免疫缺陷小鼠中消除了 TAN 的积累。我们的研究结果表明，METTL3 通过与 YTHDF2 合作并改变 TAN 浸润来调节肿瘤生长，在 PTC 致癌发生中发挥了关键的肿瘤抑制作用，从而抑制了核因子 κB（NF-κB）通路中 c-Rel 和 RelA 的失活，这扩展了我们对 m6A 修饰与肿瘤微环境可塑性之间关系的理解。
