METTL3/IGF2BP1/CD47 contributes to the sublethal heat treatment induced mesenchymal transition in HCC
METTL3/IGF2BP1/CD47 contributes to the sublethal heat treatment induced mesenchymal transition in HCC
复制标题
METTL3/IGF2BP1/CD47 有助于亚致死热处理诱导的 HCC 间质转化
DOI：
10.1016/j.bbrc.2021.01.085
复制
发表时间：
2021-02-12
影响因子：
3.1
通讯作者：
Shu, Minfeng
中科院分区：
文献类型：
--
作者：
Fan, Zhuoyang;Gao, Yang;Shu, Minfeng
微波消融术是小肝癌的一线治疗方法，但不完全消融术易引起复发和转移。然而，其潜在机制在很大程度上仍未被探索。在这里，我们报道了亚致死热处理（46℃）强烈促进HCC细胞的迁移和EMT转化。机制研究显示，与37℃相比，46℃处理的HCC细胞表达更高水平的CD47。敲低CD47显著减弱亚致死热处理刺激的迁移和EMT转变。此外，m6A修饰的关键酶METTL3也被46℃处理诱导，并在HCC细胞中触发CD47的表达。此外，进一步证明CD47 mRNA降解以igf2bp1依赖的方式稳定。重要的是，亚致死热处理在患者来源的类器官中也证实了刺激CD47表达和EMT转化。综上所述，我们的研究表明，METTL3/IGF2BP1/CD47介导的EMT转变有助于HCC细胞不完全消融诱导的转移。此外，这些发现确定了METTL3/IGF2BP1/CD47轴是微波消融的潜在治疗靶点，并为不完全热消融与RNA甲基化之间的串扰提供了新的线索。(c) 2021爱思唯尔公司版权所有。
Microwave ablation is a first-line treatment of small hepatocellular carcinoma (HCC), while incomplete ablation induces recurrence and metastasis. However, its underlying mechanism remains largely unexplored. Here we reported that sublethal heat treatment (46 degrees C) strongly promoted migration and EMT transition in HCC cells. Mechanistic investigation revealed that compared with 37 degrees C, HCC cells treated with 46 degrees C expressed higher level of CD47. Knockdown of CD47 significantly attenuated sublethal heat treatment stimulated migration and EMT transition. In addition, METTL3 which is the key enzyme of m6A modification was also induced by 46 degrees C treatment and triggered CD47 expression in HCC cells. Moreover, CD47 mRNA degradation was further proved to be stabled in the IGF2BP1-dependent manner. Importantly, sublethal heat treatment stimulated CD47 expression and EMT transition were also confirmed in patient-derived organoid. Taken together, our study suggests that METTL3/IGF2BP1/CD47 mediated EMT transition contributes to the incomplete ablation induced metastasis in HCC cells. Moreover, these findings identify the METTL3/IGF2BP1/CD47 axis as a potential therapeutic target for the microwave ablation and shed new lights on the crosstalk between incomplete heat ablation and RNA methylation. (c) 2021 Elsevier Inc. All rights reserved.