Metal Exposure Promotes Colorectal Tumorigenesis via the Aberrant N6-Methyladenosine Modification of ATP13A3,Environmental Science & Technology

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Metal Exposure Promotes Colorectal Tumorigenesis via the Aberrant N6-Methyladenosine Modification of ATP13A3
Environmental Science & Technology ( IF 10.8 ) Pub Date : 2023-02-06 , DOI: 10.1021/acs.est.2c07389
Shuwei Li _{1,

2} , Shenya Xu _{1,

2} , Yehua Chen _{1,

2} , Jieyu Zhou _{1,

2} , Shuai Ben _{1,

2} , Mengfan Guo _{1,

2} , Haiyan Chu _{1,

2} , Dongying Gu ₃ , Zhengdong Zhang _{1,

2} , Meilin Wang _{1,

2,

4}

Affiliation

Element contamination, including that from heavy metals, is associated with gastrointestinal tumorigenesis, but the effects and mechanisms of crucial element exposure associated with colorectal cancer remain unclear. We profiled 56 elements by ICP-MS and used logistic regression, LASSO, BKMR, and GAM to identify colorectal cancer-relevant elements. A series of biochemical experiments were performed to demonstrate the cytotoxicity and the mechanisms of malignant transformation after metal exposure. Using an elementomics approach, we first found that the metal thallium (Tl) was positively correlated with many toxic metals and was associated with a significantly increased risk of colorectal cancer. Acute exposure to Tl induced cytotoxicity and cell death by accelerating the generation of reactive oxygen species and DNA damage. Chronic exposure to Tl led to the inhibition of cell death and thereby induced the malignant transformation of normal colon cells and xenograft tumor formation in nude mice. Furthermore, we describe the first identification of a significant metal quantitative trait locus for the novel colorectal cancer susceptibility locus rs1511625 near ATP13A3. Mechanistically, Tl increased the level of aberrant N⁶-methyladenosine (m⁶A) modification of ATP13A3 via the METLL3/METTL14/ALKBH5-ATP13A3 axis to promote colorectal tumorigenesis. This study provides a basis for the development of public health strategies for reducing metal exposure among populations at high risk for colorectal cancer.

中文翻译：

金属暴露通过 ATP13A3 的异常 N6-甲基腺苷修饰促进结直肠肿瘤发生

元素污染，包括来自重金属的污染，与胃肠道肿瘤发生有关，但与结直肠癌相关的关键元素暴露的影响和机制仍不清楚。我们通过 ICP-MS 分析了 56 种元素，并使用逻辑回归、LASSO、BKMR 和 GAM 来识别结直肠癌相关元素。进行了一系列生化实验以证明金属暴露后的细胞毒性和恶性转化机制。使用元素组学方法，我们首先发现金属铊 (Tl) 与许多有毒金属呈正相关，并且与结直肠癌风险显着增加有关。急性暴露于 Tl 通过加速活性氧的产生和 DNA 损伤诱导细胞毒性和细胞死亡。慢性暴露于 Tl 导致细胞死亡受到抑制，从而诱导正常结肠细胞的恶性转化和裸鼠异种移植瘤的形成。此外，我们描述了首次鉴定出新的结直肠癌易感基因座 rs1511625 附近的重要金属数量性状基因座ATP13A3。从机制上讲，Tl通过METLL3 / METTL14 / ALKBH5 - ATP13A3轴增加ATP13A3的异常N ^{6 -}甲基腺苷 (m ⁶ A) 修饰水平，从而促进结直肠肿瘤发生。该研究为制定公共卫生策略以减少结直肠癌高危人群的金属暴露提供了基础。

更新日期：2023-02-06

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