Department of Internal Medicine, Texas A&M Health Science Center College of Medicine, Scott and White Hospital, Central Texas Veterans Health Care System, Temple, TX 76504, USA.
Lab Invest. 2012 Oct;92(10):1451-60. doi: 10.1038/labinvest.2012.110. Epub 2012 Aug 20.
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 nonmalignant controls. The control of MAOA expression by promoter hypermethylation was evaluated and the contribution of interleukin-6 (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 nonmalignant 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.
在胆管癌中多巴胺和 5-羟色胺的分泌增加，具有促进生长的作用。单胺氧化酶 A（MAOA）是 5-羟色胺和多巴胺的降解酶，其在胆管癌中通过未知机制受到抑制。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 表达受抑制的机制；（iii）评估恢复胆管癌细胞中 MAOA 表达的后果。评估胆管癌和非恶性对照中 MAOA 的表达。评估启动子超甲基化对 MAOA 表达的控制作用，并确定白细胞介素 6（IL-6）信号对 MAOA 表达抑制的作用。还评估了 MAOA 过表达对胆管癌细胞生长和侵袭的影响。MAOA 表达与胆管癌的分化、侵袭和生存相关。胆管癌样本和细胞系中 MAOA 启动子在起始密码子上游被超甲基化，但在非恶性对应物中没有。IL-6 信号还通过一种独立于超甲基化的机制，通过调节 SP-1 转录活性与其抑制剂 R1 阻遏物之间的平衡，降低 MAOA 表达。抑制 IL-6 信号和 DNA 甲基化均可将 MAOA 水平恢复到胆管细胞中观察到的水平。强制 MAOA 过表达抑制胆管癌细胞的生长和侵袭。MAOA 表达受启动子超甲基化和 IL-6 信号的协同控制。MAOA 可能是胆管癌管理中有用的预后标志物，旨在增加 MAOA 表达的治疗方法可能对胆管癌的治疗有益。
