Dietary and Genetic Obesity Promote Liver Inflammation and Tumorigenesis by Enhancing IL-6 and TNF Expression

Abstract

Summary Epidemiological studies indicate that overweight and obesity are associated with increased cancer risk. To study how obesity augments cancer risk and development, we focused on hepatocellular carcinoma (HCC), the common form of liver cancer whose occurrence and progression are the most strongly affected by obesity amongst all cancers. We now demonstrate that either dietary or genetic obesity is a potent bona fide liver tumor promoter in mice. Obesity-promoted HCC development was dependent on enhanced production of the tumor promoting cytokines IL-6 and TNF, which cause hepatic inflammation and activation of the oncogenic transcription factor STAT3. The chronic inflammatory response caused by obesity and enhanced production of IL-6 and TNF may also increase the risk of other cancers.

Overexpression of CYB5R3 and NQO1, two NAD+‐producing enzymes, mimics aspects of caloric restriction

“…To test this hypothesis, we treated mice with a single injection of the chemical carcinogen, diethylnitrosamine (DEN), a model of metabolic syndrome‐associated liver cancer (Park et al., 2010). Here, sixteen‐day‐old RedTg and Wt mice were injected with DEN and then put on high‐fat (HF) diet from weaning to 16 months of age.…”

“…The development and progression of liver cancer as well as the relative risk of cancer‐related deaths have been associated with chronic systemic inflammation(De Pergola & Silvestris, 2013). Interestingly, ablation of TNF signaling in mice by genetic deletion of the type 1 TNF receptor ( Tnfr1 −/− ) markedly impedes the development of obesity‐dependent liver cancer (Park et al., 2010). In our study, overexpression of CYB5R3 and NQO1 resulted in lower hepatic inflammatory signature as well as a lower level of Tnrfs18 mRNA, which encodes a member of the TNF receptor superfamily.…”

NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer

“…Infectious agents, such as Helicobactro pylori and Papillomaviruses, promote carcinogenesis (Psyrri and DiMaio, 2008;Marusawa and Chiba, 2010;Polk and Peek, 2010). Obesity, tobacco smoke and inflammatory bowel disease that act as non-infectious agents can also increase the risk of cancer development (Park et al, 2010). Studies show that infl ammatory microenvironment is as important as the tumor cell population (Mantovani, 2009).…”

β-Arrestin1 enhances hepatocellular carcinogenesis through inflammation-mediated Akt signalling

“…The exact mechanism of HCC initiation and development is still unclear, though inflammation has been shown to play a key role in this progression 2 . Inflammation-induced liver injury is a critical factor in the development of HCC.…”

“…Progression from chronic hepatitis to hepatocellular carcinoma is characterized by infiltration of immune cells and inflammatory cytokine production 5 . TNF-a, one of the most important proinflammatory cytokines, is produced predominantly by Kupffer cells and in part by neutrophils or hepatocytes during inflammatory responses; this cytokine is critical for maintenance of chronic inflammation 2 . The increased production of TNF-a may, in turn, augment the activation of inflammatory cells and mediate the release of inflammation factors, such as interleukin-1 (IL-1), IL-6 and intercellular adhesion molecule 6 .…”