Up-regulation of RNA m6A methyltransferase like-3 expression contributes to arsenic and benzo[a]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.
Up-regulation of RNA m6A methyltransferase like-3 expression contributes to arsenic and benzo[a]pyrene co-exposure-induced cancer stem cell-like property and tumorigenesis.
复制标题
RNA m6A 甲基转移酶 like-3 表达的上调有助于砷和苯并[a]芘共暴露诱导的癌症干细胞样特性和肿瘤发生。
DOI：
10.1016/j.taap.2023.116764
复制
发表时间：
2023
影响因子：
3.8
通讯作者：
Yang,Chengfeng
中科院分区：
文献类型：
--
作者：
Wang,Zhishan;Uddin,MohammadBurhan;Wang,Po-Shun;Liu,Zulong;Barzideh,David;Yang,Chengfeng
虽然单独接触砷或 BaP 会导致肺癌，但研究表明，砷和 BaP 共同接触显示出明显更强的肺部致瘤作用。然而，其根本机制尚未得到很好的理解。研究表明RNA分子经过化学修饰。真核信使 RNA 中最常见的 RNA 修饰是 N6-甲基腺苷 (m6A) 甲基化。本研究旨在确定砷加 BaP 暴露是否会改变 RNA m6A 甲基化及其在砷加 BaP 暴露的肺部致瘤作用中的作用。本研究使用砷或 BaP 单独暴露转化的人支气管上皮细胞，以及砷加 BaP 和小鼠异种移植肿瘤发生模型。结果发现，砷加 BaP 暴露的转化细胞的 RNA m6A 甲基化水平显着高于砷或单独 BaP 暴露的转化人支气管上皮细胞。蛋白质印迹分析表明，砷加 BaP 暴露可显着上调培养细胞和小鼠肺组织中 m6A writer 甲基转移酶样 3 (METTL3) 的表达水平。在砷加 BaP 暴露转化的细胞中，METTL3 敲低显着降低了其 RNA m6A 甲基化水平。功能研究表明，在砷加 BaP 暴露转化的细胞中，METTL3 敲低大大降低了其贴壁依赖性和非依赖性生长、癌症干细胞特征和肿瘤发生。这项研究的结果表明，砷和 BaP 共同暴露会导致表观转录组失调，这可能对砷和 BaP 共同暴露引起的协同肺致瘤作用有显着贡献。
While arsenic or BaP alone exposure can cause lung cancer, studies showed that arsenic plus BaP co-exposure displays a significantly stronger lung tumorigenic effect. However, the underlying mechanism has not been well understood. Studies showed that RNA molecules are chemically modified. The most frequently occurring RNA modification in eukaryotic messenger RNAs is the N6-methyladenosine (m6A) methylation. This study aimed to determine whether arsenic plus BaP exposure alters RNA m6A methylation and its role in lung tumorigenic effect of arsenic plus BaP exposure. Human bronchial epithelial cells transformed by exposure to arsenic or BaP alone, and arsenic plus BaP and mouse xenograft tumorigenesis models were used in this study. It was found that arsenic plus BaP exposure-transformed cells have significantly higher levels of RNA m6A methylation than arsenic or BaP alone exposure-transformed human bronchial epithelial cells. Western blot analysis showed that arsenic plus BaP exposure greatly up-regulates the m6A writer methyltransferase like-3 (METTL3) expression levels in cultured cells and mouse lung tissues. METTL3 knockdown in cells transformed by arsenic plus BaP exposure drastically reduced their RNA m6A methylation levels. Functional studies revealed that METTL3 knockdown in cells transformed by arsenic plus BaP exposure greatly reduces their anchorage-dependent and -independent growth, cancer stem cell characters and tumorigenesis. The findings from this study suggest that arsenic plus BaP co-exposure causes epitranscriptomic dysregulation, which may contribute significantly to arsenic plus BaP co-exposure-caused synergistic lung tumorigenic effect.