METTL3-mediated m(6)A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway.
METTL3-mediated m(6)A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway.
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METTL3介导的m6A mRNA修饰通过Notch信号通路促进食管癌的发生和进展
DOI：
10.1016/j.omtn.2021.07.007
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发表时间：
2021-12-03
期刊：
影响因子：
--
通讯作者：
Lin S
中科院分区：
文献类型：
--
作者：
Han H;Yang C;Zhang S;Cheng M;Guo S;Zhu Y;Ma J;Liang Y;Wang L;Zheng S;Wang Z;Chen D;Jiang YZ;Lin S
食管癌是一种死亡率高的致死性恶性肿瘤，但其发病的分子机制尚不清楚。在这里，我们发现n6 -甲基腺苷（m6A）甲基转移酶样3 （METTL3）在食管鳞状细胞癌（ESCC）中显著上调，并与患者预后不良相关。METTL3的缺失导致体外和体内ESCC生长和进展的减少。我们进一步利用Mettl3条件敲除小鼠建立了ESCC启动和进展模型，发现Mettl3介导的m6A修饰促进了体内ESCC的启动和进展。此外，通过METTL3过表达ESCC细胞模型和METTL3条件敲入小鼠模型，我们证明了METTL3在体外和体内促进ESCC肿瘤发生的关键功能。在机制上，mettl3催化的m6A修饰促进NOTCH1的表达和Notch信号通路的激活。Notch信号通路的强制激活成功地挽救了mettl3缺失的ESCC细胞的生长、迁移和侵袭能力。我们的数据揭示了ESCC肿瘤发生的重要机制，并为ESCC诊断和治疗新策略的发展提供了分子基础。我们提供了强有力的证据支持mettl3介导的m6A mRNA修饰在体外和体内食管鳞状细胞癌（ESCC）的发生和发展中是必不可少的。我们的数据揭示了ESCC肿瘤发生的重要机制，并为ESCC诊断和治疗新策略的开发提供了分子基础。
Esophageal cancer is a lethal malignancy with a high mortality rate, while the molecular mechanisms underlying esophageal cancer pathogenesis are still poorly understood. Here, we found that the N6-methyladenosine (m6A) methyltransferase-like 3 (METTL3) is significantly upregulated in esophageal squamous cell carcinoma (ESCC) and associated with poor patient prognosis. Depletion of METTL3 results in decreased ESCC growth and progression in vitro and in vivo. We further established ESCC initiation and progression models using Mettl3 conditional knockout mouse and revealed that METTL3-mediated m6A modification promotes ESCC initiation and progression in vivo. Moreover, using METTL3 overexpression ESCC cell model and Mettl3 conditional knockin mouse model, we demonstrated the critical function of METTL3 in promoting ESCC tumorigenesis in vitro and in vivo. Mechanistically, METTL3-catalyzed m6A modification promotes NOTCH1 expression and the activation of the Notch signaling pathway. Forced activation of Notch signaling pathway successfully rescues the growth, migration, and invasion capacities of METTL3-depleted ESCC cells. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for the development of novel strategies for ESCC diagnosis and treatment. We provided strong evidence supporting that METTL3-mediated m6A mRNA modification is essential for esophageal squamous cell carcinoma (ESCC) initiation and progression in vitro and in vivo. Our data uncovered important mechanistical insights underlying ESCC tumorigenesis and provided molecular basis for development of novel strategies for ESCC diagnosis and treatment.
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影响因子：
16.6
作者：
Natsuizaka M;Whelan KA;Kagawa S;Tanaka K;Giroux V;Chandramouleeswaran PM;Long A;Sahu V;Darling DS;Que J;Yang Y;Katz JP;Wileyto EP;Basu D;Kita Y;Natsugoe S;Naganuma S;Klein-Szanto AJ;Diehl JA;Bass AJ;Wong KK;Rustgi AK;Nakagawa H
通讯作者：
Nakagawa H
影响因子：
39.3
作者：
Yang YM;Hong P;Xu WW;He QY;Li B
通讯作者：
Li B
影响因子：
28.5
作者：
Jin, Dan;Guo, Jiwei;Su, Guoming
通讯作者：
Su, Guoming
METTL3表达减少通过m6A甲基化介导的COL3A1上调促进三阴性乳腺癌转移
影响因子：
4.7
作者：
Shi, Yu;Zheng, Chunlei;Teng, Yuee
通讯作者：
Teng, Yuee
影响因子：
12.4
作者：
Liu, Xiaochuan;Gonzalez, Gwendolyn;Wang, Yinsheng
通讯作者：
Wang, Yinsheng