Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling

Jennifer H Benbow,Kyle J Thompson,Heidi L Cope,Elizabeth Brandon-Warner,Catherine R Culberson,Krista L Bossi,Ting Li,Mark W Russo,Keith S Gersin,Iain H Mckillop,Andrew S Delemos,Laura W Schrum

doi:10.1016/j.ajpath.2015.09.015

Jennifer H Benbow, Kyle J Thompson + Show 10 more

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https://doi.org/10.1016/j.ajpath.2015.09.015

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Journal: The American Journal of Pathology	Publication Date: Nov 18, 2015
Citations: 29	License type: cc-by

Affiliation: Carolinas Medical Center

Abstract

Obesity is an independent risk factor for the development of liver fibrosis/cirrhosis and hepatocellular carcinoma (HCC). Tenascin-C (TnC), an extracellular matrix protein, is transiently expressed during tissue injury and plays a role in fibrogenesis and tumorigenesis. However, the mechanistic role of TnC signaling in the development of HCC remains unknown. We developed a diet-induced obesity HCC mouse model and examined TnC expression and liver injury. To determine the cellular mechanism of TnC signaling in promoting inflammation and hepatocyte epithelial-mesenchymal transition and migration, we used primary hepatocytes and hepatoma and macrophage cell lines. Further, to determine whether elevated TnC expression correlated with obesity-associated HCC, we measured plasma TnC in obese patients with various levels of liver injury. Increased tissue inflammation accompanied with elevated hepatic stellate cell-derived TnC and Toll-like receptor 4 expression was observed in the diet-induced obesity HCC animal model. Invitro studies found enhanced Toll-like receptor 4 signaling activated by TnC, promoting an increased inflammatory response, hepatocyte transformation, and migration. Further, obese patients with cirrhosis alone and in combination with HCC showed significant increases in plasma TnC compared with healthy volunteers and patients with less severe liver injury. Overall, these studies suggest TnC/Toll-like receptor 4 signaling as an important regulator in HCC; inhibiting this signaling axis may be a viable therapeutic target for impeding HCC.

Highlights

From the Department of Internal Medicine,* Liver Pathobiology Laboratory, the Department of Surgery,y and the Center for Liver Diseases and Liver Transplant,z Carolinas Medical Center, Charlotte, North Carolina
As reported in an earlier publication, high-fat diet (HFD) alone led to a 30% (3 of 10) tumor incidence compared with 10% (1 of 10) incidence in control diet (CD), and HFD potentiated tumor incidence in mice injected with DEN 89% (8 of 9) compared with 60% (6 of 10) in CD þ DEN.[32]
Only expression of TnC mRNA was augmented in the HFD þ DEN mice compared with the CD þ DEN mice (Figure 1A)

Summary

Introduction

We developed a diet-induced obesity HCC mouse model and examined TnC expression and liver injury. Increased tissue inflammation accompanied with elevated hepatic stellate cell-derived TnC and Toll-like receptor 4 expression was observed in the diet-induced obesity HCC animal model. Obese patients with cirrhosis alone and in combination with HCC showed significant increases in plasma TnC compared with healthy volunteers and patients with less severe liver injury. Overall, these studies suggest TnC/Toll-like receptor 4 signaling as an important regulator in HCC; inhibiting this signaling axis may be a viable therapeutic target for impeding HCC.

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