Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling
Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling
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单胺氧化酶 A 通过抑制肾上腺素能系统及其 EGFR 信号传导的反式激活来抑制肝细胞癌转移。
DOI：
10.1016/j.jhep.2014.02.025
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发表时间：
2014-06-01
影响因子：
25.7
通讯作者：
Zhang, Zhi-Gang
中科院分区：
文献类型：
--
作者：
Li, Jun;Yang, Xiao-Mei;Zhang, Zhi-Gang
背景和目标：单胺氧化酶A（Monoamine oxidase A，MAOA）是一种儿茶酚胺类神经递质降解酶，与神经精神疾病密切相关。然而，它在癌症进展中的作用仍然unknowed.Methods：肝细胞癌（HCC）组织阵列（n = 254）被用来研究MAOA表达和临床病理结果之间的相关性。通过体外侵袭和失巢凋亡实验，以及体内肝内和肺转移模型来确定MAOA在HCC转移中的作用。结果：MAOA在254例HCC组织中表达明显下调，与肿瘤血管浸润、转移及预后密切相关。然后，我们证明MAOA抑制去甲肾上腺素/肾上腺素（NE/E）诱导的肝癌侵袭和失巢凋亡抑制，并发现NE/E对肝癌行为的影响主要通过α 1A（ADRA 1A）和β 2肾上腺素能受体（ADRB 2）介导。除了经典的信号通路，这是通过肾上腺素能受体（ADR）介导的，我们发现，ADR介导的EGFR反式激活也参与NE诱导的肝癌侵袭和失巢凋亡抑制。值得注意的是，我们发现MAOA可以与EGFR抑制剂或ADR拮抗剂协同作用，消除NE诱导的HCC行为。结论：总而言之，我们的研究结果可以为MAOA作为临床结果的新型预测因子的应用提供见解，并表明增加MAOA表达或酶活性可能是一种可用于肝癌治疗的新方法。(C)2014年欧洲肝脏研究协会。由Elsevier B出版。V.保留所有权利。
Background & Aims: Monoamine oxidase A (MAOA), a catecholamine neurotransmitter degrading enzyme, is closely associated with neurological and psychiatric disorders. However, its role in cancer progression remains unknown.Methods: Hepatocellular carcinoma (HCC) tissue arrays (n = 254) were used to investigate the correlation between MAOA expression and clinicopathological findings. In vitro invasion and anoikis assays, and in vivo intrahepatic and lung metastasis models were used to determine the role of MAOA in HCC metastasis. Quantitative real-time PCR, western blotting, immunohistochemical staining and HPLC analysis were performed to uncover the mechanism of MAOA in HCC.Results: We found that MAOA expression was significantly downregulated in 254 clinical HCC samples and was closely correlated with cancer vasoinvasion, metastasis, and poor prognoses. We then demonstrated that MAOA suppressed norepinephrine/epinephrine (NE/E)-induced HCC invasion and anoikis inhibition, and uncovered that the effects of NE/E on HCC behaviors were primarily mediated through alpha 1A (ADRA1A) and beta 2 adrenergic receptors (ADRB2). In addition to the canonical signaling pathway, which is mediated via adrenergic receptors (ADRs), we found that ADR-mediated EGFR transactivation was also involved in NE-induced HCC invasion and anoikis inhibition. Notably, we found that MAOA could synergize with EGFR inhibitors or ADR antagonists to abrogate NE-induced HCC behaviors.Conclusions: Taken together, the results of our study may provide insights into the application of MAOA as a novel predictor of clinical outcomes and indicate that increasing MAOA expression or enzyme activity may be a new approach that can be used for HCC treatment. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.