title: Monoamine oxidase A suppresses hepatocellular carcinoma metastasis by inhibiting the adrenergic system and its transactivation of EGFR signaling.
abstract: OBJECTIVE
  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.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Ya-Hui
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Ming-Xuan
authors.initials: MX
authors.lastname: Feng
authors.affiliation: Department of Plastic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Xiao-Jin
authors.initials: XJ
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yan-Li
authors.initials: YL
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Shuo
authors.initials: S
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Wen-Xin
authors.initials: WX
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Jian-Ren
authors.initials: JR
authors.lastname: Gu
authors.affiliation: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: xiaqiang@shsmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xia
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zzhang@shsci.org.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000494:pharmacology; D023102:Anoikis / Q000187:drug effects / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004837:Epinephrine / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011237:Predictive Value of Tests; D011379:Prognosis; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D008996:Monoamine Oxidase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; D066246:ErbB Receptors; D009638:Norepinephrine; D004837:Epinephrine
keywords: Adrenergic receptor; EGFR; Hepatocellular carcinoma; Metastasis; Monoamine oxidase A