Chen Xiao-Yu, Liang Rui, Yi You-Cai, Fan Hui-Ning, Chen Ming, Zhang Jing, Zhu Jin-Shui
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Front Cell Dev Biol. 2021 Mar 15;9:647702. doi: 10.3389/fcell.2021.647702. eCollection 2021.
N-methyladenosine (mA) RNA methylation is implicated in the progression of multiple cancers via influencing mRNA modification. YTHDF1 can act as an oncogene in gastric cancer (GC), while the biological mechanisms via which YTHDF1 regulates gastric tumorigenesis through mA modification remain largely unknown.
GEO and TCGA cohorts were analyzed for differentially expressed mA modification components in GC clinical specimens and their association with clinical prognosis. Transwell and flow cytometry assays as well as subcutaneous xenograft and lung metastasis models were used to evaluate the phenotype of YTHDF1 in GC. Intersection of RNA/MeRIP-seq, luciferase assay, RIP-PCR, RNA pull-down and MeRIP-PCR was used to identify YTHDF1- modified USP14 and its mA levels in GC cells.
High-expressed YTHDF1 was found in GC tissues and was related to poor prognosis, acting as an independent prognostic factor of poor survival in GC patients. YTHDF1 deficiency inhibited cell proliferation and invasion (), and gastric tumorigenesis and lung metastasis () and also induced cell apoptosis. Intersection assays revealed that YTHDF1 promoted USP14 protein translation in an mA-dependent manner. USP14 upregulation was positively correlated with YTHDF1 expression and indicated a poor prognosis in GC.
Our data suggested that mA reader YTHDF1 facilitated tumorigenesis and metastasis of GC by promoting USP14 protein translation in an mA-dependent manner and might provide a potential target for GC treatment.
N-甲基腺苷（mA）RNA甲基化通过影响mRNA修饰参与多种癌症的进展。YTHDF1在胃癌（GC）中可作为一种癌基因，而YTHDF1通过mA修饰调节胃癌发生的生物学机制仍 largely未知。
分析GEO和TCGA队列中GC临床标本中差异表达的mA修饰成分及其与临床预后的关系。采用Transwell和流式细胞术分析以及皮下异种移植和肺转移模型来评估YTHDF1在GC中的表型。通过RNA/MeRIP-seq、荧光素酶测定、RIP-PCR、RNA下拉和MeRIP-PCR的交集来鉴定GC细胞中YTHDF1修饰的USP14及其mA水平。
在GC组织中发现高表达的YTHDF1，且与预后不良相关，是GC患者生存不良的独立预后因素。YTHDF1缺陷抑制细胞增殖和侵袭（）以及胃癌发生和肺转移（），并诱导细胞凋亡。交集分析显示YTHDF1以mA依赖的方式促进USP14蛋白翻译。USP14上调与YTHDF1表达呈正相关，提示GC预后不良。
我们的数据表明，mA阅读器YTHDF1通过以mA依赖的方式促进USP14蛋白翻译促进GC的肿瘤发生和转移，可能为GC治疗提供潜在靶点。
