Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S.
Bile acid reflux contributes to development of esophageal adenocarcinoma via activation of phosphatidylinositol-specific phospholipase Cgamma2 and NADPH oxidase NOX5-S.
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胆汁酸反流通过激活磷脂酰肌醇特异性磷脂酶 Cgamma2 和 NADPH 氧化酶 NOX5-S 促进食管腺癌的发展。
DOI：
10.1158/0008-5472.can-09-2774
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发表时间：
2010-02-01
期刊：
影响因子：
11.2
通讯作者：
Cao W
中科院分区：
文献类型：
--
作者：
Hong J;Behar J;Wands J;Resnick M;Wang LJ;Delellis RA;Lambeth D;Cao W
胃食道反流病合并Barrett‘s食道(BE)是食管腺癌(EA)的主要危险因素。然而，从BE到EA的过程机制尚不完全清楚。除酸反流外，胆汁酸反流也可能在BE向EA的发展过程中发挥重要作用。在这项研究中，我们研究了磷脂酰肌醇特异性磷脂酶C(PI-PLC)和一种新的NADPH氧化酶NOX5-S在胆汁酸诱导的细胞增殖中的作用。我们发现牛磺酸脱氧胆酸能显著促进EA细胞NOX5-S的表达、H_2O_2的产生和细胞的增殖。PI-PLC的阻断剂U73122可显著抑制TDCA诱导的细胞增殖。免疫印迹法检测到β-1、β-3、β-4、γ-1和γ-2，未检测到β-2和δ-1。用siRNAs敲除PI-PLCNOX2或γ-2MAPK，可显著降低TDCA诱导的NOX5-S表达增加、H_2O_2产生和细胞增殖。而PI-PLCβ-1、β-3、β-4、γ-1或ERK-1的MAPK-1表达下调则无明显作用。TdCA显著增加ERK2的磷酸化，U73122或PI-PLCγ2siRNA可抑制这种作用。结论：TDCA诱导EA细胞NOX5-S表达增加和细胞增殖可能依赖于PI-PLCERK2和γ-2MAPK的顺序激活。提示Barrett‘s食管炎患者存在的胆汁酸反流可能通过激活PI-PLCNOX2、γ-2MAPK和NADPH5-S等途径，促进ROS的产生和细胞的增殖，从而参与EA的发生发展。
Gastroesophageal reflux disease complicated by Barrett’s esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). However, the mechanisms of the progression from BE to EA are not fully understood. Besides acid reflux, bile acid reflux may also play an important role in the progression from BE to EA. In this study we examined the role of phosphatidylinositol-specific phospholipase C (PI-PLC) and a novel NADPH oxidase NOX5-S in bile acid-induced in cell proliferation. We found that taurodeoxycholic acid (TDCA) significantly increased NOX5-S expression, H2O2 production and cell proliferation in EA cells. The TDCA-induced increase in cell proliferation was significantly reduced by U73122, an inhibiter of PI-PLC. PI-PLCβ1, β3, β4, γ1 and γ2, but not β2 and δ1 were detectable in FLO cells by Western blot analysis. Knockdown of PI-PLCγ2 or ERK-2 MAP kinase with siRNAs significantly decreased TDCA-induced increase in NOX5-S expression, H2O2 production and cell proliferation. In contrast, knockdown of PI-PLC β1, β3, β4, γ1 or ERK-1 MAP kinase had no significant effect. TDCA significantly increased ERK-2 phosphorylation, an increase which was reduced by U73122 or PI-PLCγ2 siRNA. We conclude that TDCA-induced increase in NOX5-S expression and cell proliferation may depend on sequential activation of PI-PLCγ2 and ERK-2 MAP kinase in EA cells. It is possible that bile acid reflux present in patients with Barrett’s esophagus may increase ROS production and cell proliferation via activation of PI-PLCγ2, ERK-2 MAP kinase and NADPH oxidase NOX5-S, thereby contributing to the development of EA.