To elucidate the mechanisms leading from obesity and steatosis to HCC, Park et al. in their recent article, applied the well-established DEN model for selleck inhibitor tumor induction in wild-type mice.9 They first demonstrated that mice kept on a HFD exhibited greatly enhanced HCC development compared to nonobese mice when treated with DEN. In line with these findings, Park et al. described that also leptin-deficient obese mice display greatly enhanced HCC development relative to wild-type mice after administration

of DEN. DEN-related tumor induction was previously linked to enhanced hepatocyte death and thereby compensatory hepatocyte proliferation.10 Conversely, Park et al. describe reduced apoptosis and enhanced cell proliferation in HCC of obese mice as compared to HCC of mice placed on a low-fat diet. In line with these findings, transplantation of hepatoma

cells into lean mice that were placed on low-fat diet/HFD after inoculation of the cells revealed that the degree of host obesity determined tumor growth. This suggests that alterations in signal transduction pathways that modulate tumor cell proliferation independently of liver damage and compensatory proliferation may underlie the tumor-promoting effect of obesity. Indeed, Park et al. describe elevated c-Jun N-terminal kinase (JNK) activity and increased phosphorylation of the mammalian target of rapamycin (mTOR) target S6 kinase and its substrate ribosomal protein S6 in obese mice. Furthermore, HCCs in obese mice exhibited greatly elevated activity of both pro-oncogenic and inflammatory pathways such as extracellular

signal-regulated kinase (ERK) and signal transducer PR-171 supplier and activator of transcription 3 (STAT3). Obesity also enhanced interleukin-6 (IL-6) messenger RNA and tumor necrosis factor (TNF) 上海皓元 and IL-1b expression in both nontumor liver and HCC. As a corroboration of these data, growth of transplanted hepatoma cells can be slowed by administration of a JAK (Janus kinase) inhibitor that prevents STAT3 activation. Enhanced activity of STAT3, a major transcriptional target for IL-6, was previously linked to development of HCC in humans. Furthermore, He et al. demonstrated that IL-6 is required for HCC development and that circulating IL-6 is elevated in cirrhosis and HCC.11 In their study,9 Park et al. used IL-6−/− mice to elucidate whether IL-6 is an important component of tumor promotion in the context of obesity. As previously described, deletion of IL-6 protected mice from DEN-induced HCC development when the mice were kept on a low-fat diet. Furthermore, no increase in tumor formation and growth was observed when these mice were in kept on a HFD. Interestingly tumor load in male IL-6-/- mice was similar to that of wild-type female mice, but unlike wild-type females, which develop more HCC when rendered obese, no significant increase in tumor load was described in obese IL-6-/- males.