Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.
Monoamine oxidase A expression is suppressed in human cholangiocarcinoma via coordinated epigenetic and IL-6-driven events.
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DOI：
10.1038/labinvest.2012.110
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发表时间：
2012-10
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影响因子：
--
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中科院分区：
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--
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胆管癌中多巴胺和5-羟色胺的分泌增加，具有促生长作用。单胺氧化酶A（MAOA），5-羟色胺和多巴胺的降解酶，通过未知的机制在胆管癌中被抑制。本研究的目的是（i）将MAOA免疫反应性与胆管癌的病理生理参数相关联，（ii）确定MAOA表达被抑制的机制，（iii）评估胆管癌中MAOA表达恢复的后果。在胆管癌和非恶性对照中评估MAOA表达。通过启动子超甲基化来评估MAOA表达的控制，并确定IL-6信号传导对MAOA表达抑制的贡献。还评估了MAOA过表达对胆管癌生长和侵袭的影响。MAOA的表达与胆管癌的分化程度、侵袭性和生存期有关。在胆管癌样品和细胞系中，MAOA启动子在起始密码子的上游立即高甲基化，但在非恶性对应物中没有。IL-6信号还通过一种不依赖于超甲基化的机制降低MAOA表达，该机制涉及调节SP-1转录活性及其抑制剂R1阻遏物之间的平衡。抑制IL-6信号传导和DNA甲基化使MAOA水平恢复到在胆管细胞中观察到的水平。强制MAOA过表达抑制胆管癌的生长和侵袭。启动子超甲基化和IL-6信号传导的协调控制抑制了MAOA表达。MAOA可能是一个有用的预后标志物在胆管癌的管理，和治疗设计，以增加MAOA表达可能证明有益的胆管癌的治疗。
The secretion of dopamine and serotonin is increased in cholangiocarcinoma, which has growth-promoting effects. Monoamine oxidase A (MAOA), the degradation enzyme of serotonin and dopamine, is suppressed in cholangiocarcinoma via an unknown mechanism. The aims of this study were to (i) correlate MAOA immunoreactivity with pathophysiological parameters of cholangiocarcinoma, (ii) determine the mechanism by which MAOA expression is suppressed and (iii) evaluate the consequences of restored MAOA expression in cholangiocarcinoma. MAOA expression was assessed in cholangiocarcinoma and non-malignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of IL-6 signaling to the suppression of MAOA expression was determined. The effects of MAOA overexpression on cholangiocarcinoma growth and invasion were also assessed. MAOA expression is correlated with differentiation, invasion and survival in cholangiocarcinoma. The MAOA promoter was hypermethylated immediately upstream of the start codon in cholangiocarcinoma samples and cell lines but not in non-malignant counterparts. IL-6 signaling also decreased MAOA expression via a mechanism independent of hypermethylation, involving the regulation of the balance between SP-1 transcriptional activity and its inhibitor, R1 repressor. Inhibition of both IL-6 signaling and DNA methylation restored MAOA levels to those observed in cholangiocytes. Forced MAOA overexpression inhibited cholangiocarcinoma growth and invasion. MAOA expression is suppressed by the coordinated control of promoter hypermethylation and IL-6 signaling. MAOA may be a useful prognostic marker in the management of cholangiocarcinoma, and therapies designed to increase MAOA expression might prove beneficial in the treatment of cholangiocarcinoma.
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DOI：
10.1073/pnas.0601515103
发表时间：
2006-07-18
影响因子：
11.1
作者：
Ou, Xiao-Ming;Chen, Kevin;Shih, Jean C.
通讯作者：
Shih, Jean C.
影响因子：
3.4
作者：
Pietrangeli, P;Mondovì, B
通讯作者：
Mondovì, B
影响因子：
3.5
作者：
Pinsonneault, Julia K.;Papp, Audrey C.;Sadee, Wolfgang
通讯作者：
Sadee, Wolfgang
影响因子：
13.5
作者：
Yokomuro, S;Tsuji, H;Demetris, AJ
通讯作者：
Demetris, AJ
影响因子：
6.4
作者：
SHIMIZU, Y;DEMETRIS, AJ;WHITESIDE, TL
通讯作者：
WHITESIDE, TL