Adiponectin Modulates C-Jun N-Terminal Kinase and Mammalian Target of Rapamycin and Inhibits Hepatocellular Carcinoma

BACKGROUND & AIMS: 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.