Bile acid receptor TGR5, NADPH Oxidase NOX5-S and CREB Mediate Bile Acid-Induced DNA Damage In Barrett's Esophageal Adenocarcinoma Cells.
Bile acid receptor TGR5, NADPH Oxidase NOX5-S and CREB Mediate Bile Acid-Induced DNA Damage In Barrett's Esophageal Adenocarcinoma Cells.
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DOI：
10.1038/srep31538
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发表时间：
2016-08-11
影响因子：
4.6
通讯作者：
Cao W
中科院分区：
文献类型：
--
作者：
Li D;Cao W
胆汁酸反流可能加速从巴雷特食管（BE）向食管腺癌（EA）进展的机制尚未完全了解。在这项研究中，我们发现，胆汁酸牛磺脱氧胆酸（TDCA）显着增加FLO-1 EA细胞中的尾矩（TM）和组蛋白H2 AX磷酸化，TGR 5的敲低显着降低的增加。TGR 5的过表达显著增加TDCA诱导的TM增加和H2 AX磷酸化。此外，NADPH氧化酶抑制剂二苯碘鎓显着抑制TDCA诱导的TM和H2 AX磷酸化的增加。TDCA诱导的TM和H2 AX磷酸化的增加通过敲低NOX 5-S而显著降低，并且NOX 5-S的过表达显著增加TDCA诱导的尾矩和H2 AX磷酸化的增加。此外，TDCA显着增加cAMP反应元件结合蛋白（CREB）磷酸化在FLO-1细胞。CREB的敲低显著降低TDCA诱导的NOX 5-S mRNA和尾矩的增加。相反，CREB的过度表达显著增加TDCA诱导的TM增加。TDCA诱导的DNA损伤可能依赖于TGR 5、CREB和NOX 5-S的激活。在巴雷特患者中，胆汁酸可能通过激活TGR 5和CREB激活NOX 5-S并增加活性氧（ROS）的产生。NOX 5-S衍生的ROS可能导致DNA损伤，从而促进BE向EA的进展。
The mechanisms whereby bile acid reflux may accelerate the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. In this study we found that bile acid taurodeoxycholic acid (TDCA) significantly increased the tail moment (TM) and histone H2AX phosphorylation in FLO-1 EA cells, an increase which was significantly decreased by knockdown of TGR5. Overexpression of TGR5 significantly increased TDCA-induced TM increase and H2AX phosphorylation. In addition, NADPH oxidase inhibitor diphenylene iodonium significantly inhibited the TDCA-induced increase in TM and H2AX phosphorylation. TDCA-induced increase in TM and H2AX phosphorylation was significantly decreased by knockdown of NOX5-S and overexpression of NOX5-S significantly increased TDCA-induced increase in the tail moment and H2AX phosphorylation. Furthermore, TDCA significantly increased cAMP response element binding protein (CREB) phosphorylation in FLO-1 cells. Knockdown of CREB significantly decreased TDCA-induced increase in NOX5-S mRNA and the tail moment. Conversely, overexpression of CREB significantly increased TDCA-induced TM increase. We conclude that TDCA-induced DNA damage may depend on the activation of TGR5, CREB and NOX5-S. It is possible that in Barrett’s patients bile acids may activate NOX5-S and increase reactive oxygen species (ROS) production via activation of TGR5 and CREB. NOX5-S-derived ROS may cause DNA damage, thereby contributing to the progression from BE to EA.