The Missing Link between Obesity and Hepatocellular Carcinoma: IL-6-Mediated STAT-3 Activation as a Key Player in Hepatocarcinogenesis

ducer and activator of transcription 3 (STAT3) in the development of obesitylinked HCC is a novel mechanism of great importance which could open up new diagnostic and therapeutic avenues. STAT3, which is a well-known transcription factor that also plays a master regulatory role in body weight regulation and glucose homeostasis, has been linked to the proliferation, invasion, angiogenesis, progression and survival of human cancers through the upregulation of target proto-oncogenes of several human cancers, including HCC [2–4] . It was initially described as a DNA-binding activity from IL-6-stimulated hepatocytes, capable of selectively interacting with an enhancer element in the promoter of acute-phase genes, which is also known as the acutephase response element [5] . Although a possible association between liver fat accumulation and HCC development has long been known [6, 7] , Park et al. [8] were the first to demonstrate that either dietary or genetic obesity is a direct promoter of HCC development in mice. They also demonstrated that one of the mechanisms that account for the tumor-promoting effect of obesity is the low-grade inflammatory response it induces, which results in an elevated production of cytokines, such Dear Sir, We read with interest the comprehensive review by Wree et al. [1] on the relationship between obesity and liver tissue. The authors successfully reviewed the current knowledge on the link between adipocytes and hepatocytes with a special emphasis on the contribution of inflammation and cytokines to the pathogenesis. Although possible mechanisms behind this association, especially the link between obesity and hepatocellular carcinoma (HCC), were brilliantly discussed in the light of pertinent literature, we would like to mention a novel mechanism relating obesity with HCC, which we think is important for gaining insight into the cellular mechanisms involved in the pathogenesis. In their review, the authors mentioned a wide range of possible factors that facilitate progression from obesity to HCC. They also proposed that the main factor that promotes cancer development is leptin. Leptin was shown to promote angiogenesis and facilitate progression of nonalcoholic steatohepatitis to HCC. It is capable of activating multiple signal transduction pathways, such as JNK, protein kinase B, the AKT pathway, and the extracellular signal-regulated kinase pathway in HCC [1] . Although not mentioned by the authors, IL-6-activated signal transPublished online: May 27, 2011