title: Lycopene attenuated hepatic tumorigenesis via differential mechanisms depending on carotenoid cleavage enzyme in mice.
abstract: Obesity is associated with increased liver cancer risks and mortality. We recently showed that apo-10'-lycopenoic acid, a lycopene metabolite generated by beta-carotene-9',10'-oxygenase (BCO2), inhibited carcinogen-initiated, high-fat diet (HFD)-promoted liver inflammation, and hepatic tumorigenesis development. The present investigation examined the outstanding question of whether lycopene could suppress HFD-promoted hepatocellular carcinoma (HCC) progression, and if BCO2 expression is important using BCO2-knockout (BCO2-KO) and wild-type male mice. Results showed that lycopene supplementation (100 mg/kg diet) for 24 weeks resulted in comparable accumulation of hepatic lycopene (19.4 vs. 18.2 nmol/g) and had similar effects on suppressing HFD-promoted HCC incidence (19% vs. 20%) and multiplicity (58% vs. 62%) in wild-type and BCO2-KO mice, respectively. Intriguingly, lycopene chemopreventive effects in wild-type mice were associated with reduced hepatic proinflammatory signaling (phosphorylation of NK-κB p65 and STAT3; IL6 protein) and inflammatory foci. In contrast, the protective effects of lycopene in BCO2-KO but not in wild-type mice were associated with reduced hepatic endoplasmic reticulum stress-mediated unfolded protein response (ER(UPR)), through decreasing ER(UPR)-mediated protein kinase RNA-activated like kinase-eukaryotic initiation factor 2α activation, and inositol requiring 1α-X-box-binding protein 1 signaling. Lycopene supplementation in BCO2-KO mice suppressed oncogenic signals, including Met mRNA, β-catenin protein, and mTOR complex 1 activation, which was associated with increased hepatic microRNA (miR)-199a/b and miR214 levels. These results provided novel experimental evidence that dietary lycopene can prevent HFD-promoted HCC incidence and multiplicity in mice, and may elicit different mechanisms depending on BCO2 expression.
authors.affiliation: Nutrition and Cancer Biology Lab, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.
authors.forename: Blanche C
authors.initials: BC
authors.lastname: Ip
authors.affiliation: Nutrition and Cancer Biology Lab, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts.
authors.forename: Chun
authors.initials: C
authors.lastname: Liu
authors.affiliation: Nutrition and Cancer Biology Lab, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts.
authors.forename: Lynne M
authors.initials: LM
authors.lastname: Ausman
authors.affiliation: Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Johannes
authors.initials: J
authors.lastname: von Lintig
authors.affiliation: Nutrition and Cancer Biology Lab, Jean Mayer USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts. Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts. xiang-dong.wang@tufts.edu.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Wang
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002338:Carotenoids / Q000008:administration & dosage*; D002471:Cell Transformation, Neoplastic; D059305:Diet, High-Fat; D019587:Dietary Supplements; D049308:Dioxygenases / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000077276:Lycopene; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D016588:Anticarcinogenic Agents; D012333:RNA, Messenger; D002338:Carotenoids; D049308:Dioxygenases; C481678:Bco2 protein, mouse; D000077276:Lycopene