title: Adiponectin modulates C-jun N-terminal kinase and mammalian target of rapamycin and inhibits hepatocellular carcinoma.
abstract: OBJECTIVE
  Epidemiological studies have shown that obesity is a risk factor for hepatocellular carcinoma (HCC). Lower adiponectin levels are associated with poor prognosis in obese HCC patients, hence it is plausible that adiponectin acts as a negative regulator of HCC. We investigated the effects of adiponectin on HCC development and its molecular mechanisms.
  
  
  METHODS
  Assays with Huh7 and HepG2 HCC cells were used to examine the signal transduction pathways involved in the protective functions of adiponectin in HCC. These studies were followed by in vivo approaches using HCC xenografts and tumor analysis. Results from in vitro and in vivo findings were corroborated using human HCC tissue microarray and analysis of clinicopathological characteristics.
  
  
  RESULTS
  Adiponectin increased apoptosis of HCC cells through activation of caspase-3. Adiponectin increased phosphorylation of c-Jun-N-terminal kinase (JNK) and inhibition of c-Jun-N-terminal kinase-phosphorylation inhibited adiponectin-induced apoptosis and caspase-3 activation. Adiponectin increased phosphorylation of 5'-adenosine monophosphate-activated protein kinase and tumor suppressor tuberous sclerosis complex 2 and inhibited mammalian target of rapamycin phosphorylation. Inhibition of 5'-adenosine monophosphate-activated protein kinase phosphorylation not only inhibited adiponectin-induced c-Jun-N-terminal kinase phosphorylation, but also blocked biological effects of adiponectin. Adiponectin substantially reduced liver tumorigenesis in nude mice. Importantly, analysis of adiponectin expression levels in tissue microarray of human HCC patients revealed an inverse correlation of adiponectin expression with tumor size.
  
  
  CONCLUSIONS
  Adiponectin protects against liver tumorigenesis; its reduced expression is associated with poor prognosis in obese patients with HCC.
authors.affiliation: Division of Digestive Diseases, Department of Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA. nksaxen@emory.edu
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Saxena
authors.forename: Ping P
authors.initials: PP
authors.lastname: Fu
authors.forename: Arumugam
authors.initials: A
authors.lastname: Nagalingam
authors.forename: Jason
authors.initials: J
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Handy
authors.forename: Cynthia
authors.initials: C
authors.lastname: Cohen
authors.forename: Mourad
authors.initials: M
authors.lastname: Tighiouart
authors.forename: Dipali
authors.initials: D
authors.lastname: Sharma
authors.forename: Frank A
authors.initials: FA
authors.lastname: Anania
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D012334:RNA, Neoplasm / Q000235:genetics; D054419:Receptors, Adiponectin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: D052242:Adiponectin; D012334:RNA, Neoplasm; D054419:Receptors, Adiponectin; D048031:JNK Mitogen-Activated Protein Kinases