Cytochrome P450 2A13 mediates the neoplastic transformation of human bronchial epithelial cells at a low concentration of aflatoxin B1
Cytochrome P450 2A13 mediates the neoplastic transformation of human bronchial epithelial cells at a low concentration of aflatoxin B1
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细胞色素P450 2A13在低浓度黄曲霉毒素B1下介导人支气管上皮细胞的肿瘤转化
DOI：
10.1002/ijc.28489
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发表时间：
2014-04
影响因子：
6.4
通讯作者：
Wang, Shou-Lin
中科院分区：
文献类型：
--
作者：
Wang, Yun;Wang, Xichen;Wang, Xinru;Wang, Shou-Lin
细胞色素P450 2A 13（CYP 2A 13）主要表达于人呼吸道，在黄曲霉毒素B1（AFB 1）的代谢活化中发挥重要作用，并被认为在空气中AFB 1暴露的肺癌发生中发挥重要作用。为了验证这一假设，我们将稳定表达CYP 2A 13（B-2A 13）、CYP 1A 2（B-1A 2）和CYP 2A 6（B-2A 6）的人支气管上皮（BEAS-2 B）细胞暴露于0.1-10 nM AFB 1中30-50代。B-2A 13细胞对0.1 nM AFB 1诱导的肿瘤转化表现出增加的敏感性，并且在第30代（P30）时观察到裸小鼠中的肿瘤形成，而在P50时则发生在B-1A 2细胞中。与载体对照相似，B-2A 6在该条件下未显示肿瘤转化。此外，转化的P40 B-2A 13中AFB 1-DNA加合物和8-OHdG显著增加，与p-ATR、p-BRCA 1、Mre 11、Rad 50和Rad 51的上调平行。而P40细胞凋亡接近正常，Bax、C-Caspase 3和C-PARP表达呈传代依赖性增加。抑制ATR（ATR siRNA或NU 6027）可增加P40 B-2A 13细胞的凋亡，同时上调Bax、C-Caspase 3和C-PARP，表明ATR通过抗凋亡在维持细胞存活中起重要作用。此外，ATR的激活是肿瘤转化所必需的，因为P40细胞中ATR的阻断抑制了DNA损伤修复反应和锚定非依赖性生长。我们的数据表明，CYP 2A 13在AFB 1诱导的肿瘤转化中起关键作用。ATR介导的细胞凋亡和DNA损伤修复功能障碍可能参与其中。这些结果有助于建立空气中AFB 1和人类呼吸道癌之间的联系。
Cytochrome P450 2A13 (CYP2A13), mainly expressed in human respiratory tract, is highly efficient in the metabolic activation of aflatoxin (AF) B1 (AFB1) and is assumed to play a role in human lung tumorigenesis in airborne AFB1 exposure. To validate the assumption, we exposed human bronchial epithelial (BEAS‐2B) cells stably expressing CYP2A13 (B‐2A13), CYP1A2 (B‐1A2) and CYP2A6 (B‐2A6) to 0.1–10 nM AFB1 for 30–50 passages. B‐2A13 cells showed increased sensitivity to 0.1 nM AFB1‐induced neoplastic transformation and the formation of tumors in nude mice were observed at passage 30 (P30) while it occurred at P50 B‐1A2 cells. B‐2A6, similar to vector control, showed no neoplastic transformation in this condition. Additionally, AFB1‐DNA adducts and 8‐OHdG significantly increased in transformed P40 B‐2A13, in parallel with the upregulation of p‐ATR, p‐BRCA1, Mre11, Rad50 and Rad51. However, the apoptosis of P40 cells was near normal, while the expression of Bax, C‐Caspase 3 and C‐PARP increased passage‐dependently. Inhibition of ATR (ATR siRNA or NU6027) reversely increased the apoptosis of P40 B‐2A13 cells in parallel with the upregulation of Bax, C‐Caspase 3 and C‐PARP, suggesting that ATR plays an important role in maintaining cell survival via antiapoptosis. Additionally, activation of ATR was necessary to neoplastic transformation since blockage of ATR in P40 cells inhibited DNA damage repair response and anchorage‐independent growth. Our data demonstrated that CYP2A13 played a critical role in AFB1‐induced neoplastic transformation. ATR‐mediated the dysfunction of apoptosis and DNA damage repair might be involved. These results help establish a linkage between airborne AFB1 and human respiratory carcinoma.
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影响因子：
10.4
作者：
Autrup JL;Schmidt J;Autrup H
通讯作者：
Autrup H
DOI：
--
发表时间：
2007-12
期刊：
Biomedical and environmental sciences : BES
影响因子：
--
作者：
Jun Wang;Xiu-mei Liu
通讯作者：
Jun Wang;Xiu-mei Liu
DOI：
10.1891/9780826121646.0002
发表时间：
2018-09
期刊：
Cancer Rehabilitation
影响因子：
--
作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
通讯作者：
K. Miller;R. Siegel;R. Khan;A. Jemal
工作组报告：减少发展中国家黄曲霉毒素暴露的公共卫生策略。
影响因子：
10.4
作者：
Strosnider, Heather;Azziz-Baumgartner, Eduardo;Banziger, Marianne;Bhat, Ramesh V;Breiman, Robert;Brune, Marie-Noel;DeCock, Kevin;Dilley, Abby;Groopman, John;Hell, Kerstin;Henry, Sara H;Jeffers, Daniel;Jolly, Curtis;Jolly, Pauline;Kibata, Gilbert N;Lewis, Lauren;Liu, Xiumei;Luber, George;McCoy, Leslie;Mensah, Patience;Miraglia, Marina;Misore, Ambrose;Njapau, Henry;Ong, Choon-Nam;Onsongo, Mary T K;Page, Samuel W;Park, Douglas;Patel, Manish;Phillips, Timothy;Pineiro, Maya;Pronczuk, Jenny;Rogers, Helen Schurz;Rubin, Carol;Sabino, Myrna;Schaafsma, Arthur;Shephard, Gordon;Stroka, Joerg;Wild, Christopher;Williams, Jonathan T;Wilson, David
通讯作者：
Wilson, David
影响因子：
3.9
作者：
Bao, ZP;He, XY;Hong, JY
通讯作者：
Hong, JY