FLT1 hypermethylation is involved in polycyclic aromatic hydrocarbons-induced cell transformation
FLT1 hypermethylation is involved in polycyclic aromatic hydrocarbons-induced cell transformation
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FLT1高甲基化参与多环芳烃诱导的细胞转化
DOI：
10.1016/j.envpol.2019
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发表时间：
2019-09-01
影响因子：
8.9
通讯作者：
Chen, Wen
中科院分区：
文献类型：
--
作者：
He, Zhini;Zhang, Rui;Chen, Wen
焦炉排放物（COEs）是职业环境中常见的颗粒污染物，其主要成分是多环芳烃（PAHs）。此前，我们通过全基因组甲基化阵列鉴定了苯并芘 (BaP) 诱导的细胞转化过程中 fms 相关酪氨酸激酶 1 (FLT1) 基因的异常甲基化。为了量化 FLT1 甲基化，我们建立了亚硫酸氢盐焦磷酸测序测定法，并检查了几种人类癌症中的 FLT1 高甲基化。结果显示，与邻近组织相比，70.0%（21/30 对）的肺癌含有高甲基化的 FLT1 并伴有基因表达抑制。这意味着FLT1高甲基化可能在恶性细胞转化中发挥作用。此外，COEs治疗后，原代人淋巴细胞中出现FLT1高甲基化和基因抑制，并以剂量反应的方式出现。为了探讨 FLT1 甲基化是否与 COE 暴露和 DNA 损伤相关，我们招募了 144 名暴露于高水平 COE 的男性受试者和 84 名男性对照受试者。值得注意的是，与对照组（16.8 +/- 2.8%）相比，COE暴露组（19.8 +/- 3.2%）的外周血淋巴细胞（PBLC）中FLT1甲基化增强了17.9%（P < 0.001）。 FLT1 甲基化状态与尿 1-羟基芘 (1-OHP) 水平呈正相关，尿 1-羟基芘 (1-OHP) 水平是 PAH 的内暴露标志物 (β = 0.029，95% CI = 0.010-0.048，P = 0.003)，与 DNA 损伤呈正相关 (β(OTM) = 0.024，95% CI = 0.007-0.040，P = 0.005；β(Tail) (DNA) = 0.035，95% CI = 0.0017-0.054，P < 0.001）由彗星测定表明。总而言之，这些发现表明 FLT1 可能是一种肿瘤抑制因子，其高甲基化可能导致 PAH 诱导的致癌性。 (C) 2019 Elsevier Ltd. 保留所有权利。
Coke oven emissions (COEs) are common particle pollutants in occupational environment and the major constituents of COEs are polycyclic aromatic hydrocarbons (PAHs). Previously, we identified aberrant methylation of the fms related tyrosine kinase 1 (FLT1) gene over the course of benzo(a)pyrene (BaP)-induced cell transformation via genome-wide methylation array. To quantify FLT1 methylation, we established a bisulfite pyrosequencing assay and examined the FLT1 hypermethylation in several human cancers. The results revealed that 70.0% (21/30 pairs) of lung cancers harbored hypermethylated FLT1 and concomitant suppression of gene expression compared to the adjacent tissues. This implies that FLT1 hypermethylation might play a role in malignant cell transformation. In addition, FLT1 hypermethylation and gene suppression appeared in primary human lymphocytes in a dose-response manner following COEs treatment. To explore whether FLT1 methylation is correlated with COEs exposure and DNA damage, we recruited 144 male subjects who had been exposed to high levels of COEs and 84 male control subjects. Notably, the FLT1 methylation in peripheral blood lymphocytes (PBLCs) of the COEs-exposed group (19.8 +/- 3.2%) was enhanced by 17.9% compared to that of the control group (16.8 +/- 2.8%) (P < 0.001). The FLT1 methylation status was positively correlated with urinary 1-hydroxypyrene (1-OHP) levels, an internal exposure marker of PAHs (beta = 0.029, 95% CI = 0.010-0.048, P = 0.003) and positively correlated with DNA damage (beta(OTM) = 0.024, 95% CI = 0.007-0.040, P = 0.005; beta(Tail) (DNA) = 0.035, 95% CI = 0.0017-0.054, P < 0.001) indicated by comet assay. Taken together, these findings indicate that FLT1 might be a tumor suppressor, and its hypermethylation might contribute to PAHs-induced carcinogenicity. (C) 2019 Elsevier Ltd. All rights reserved.