title: Diet-Induced Obesity Enhances Progression of Hepatocellular Carcinoma through Tenascin-C/Toll-Like Receptor 4 Signaling.
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. In vitro 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.
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Benbow
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Thompson
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Cope
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brandon-Warner
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Catherine R
authors.initials: CR
authors.lastname: Culberson
authors.affiliation: Center for Liver Diseases and Liver Transplant, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Krista L
authors.initials: KL
authors.lastname: Bossi
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Ting
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Liver Diseases and Liver Transplant, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Russo
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Keith S
authors.initials: KS
authors.lastname: Gersin
authors.affiliation: Department of Surgery, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Iain H
authors.initials: IH
authors.lastname: McKillop
authors.affiliation: Center for Liver Diseases and Liver Transplant, Carolinas Medical Center, Charlotte, North Carolina.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: deLemos
authors.affiliation: Department of Internal Medicine, Liver Pathobiology Laboratory, Carolinas Medical Center, Charlotte, North Carolina. Electronic address: laura.schrum@carolinashealthcare.org.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Schrum
mesh_terms: D000328:Adult; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D019063:Tenascin / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D019063:Tenascin; D051197:Toll-Like Receptor 4