title: Lipid rafts promote liver cancer cell proliferation and migration by up-regulation of TLR7 expression.
abstract: Hepatocellular carcinoma (HCC) occurs predominantly in patients with underlying chronic liver disease and cirrhosis. Toll-like receptors (TLRs) play an important role in innate immune responses and TLR signaling has been associated with various chronic liver diseases. Lipid rafts provide the necessary microenvironment for certain specialized signaling events to take place, such as the innate immune recognition. The purpose of this study was to determine the pattern of TLR7 expression in HCC, how to recruit TLR7 into lipid rafts responded to ligands and whether targeting TLR7 might have beneficial effects. The study group was comprised of 130 human liver tissues: 23 chronic hepatitis B (CHB), 18 liver cirrhosis (LC), 68 HCC and 21 normal livers. The expression of TLR7 was evaluated using immunohistochemistry, western blotting, and flow cytometry. Proliferation and migration of human HepG2 cells were studied following stimulation of TLR7 using the agonist gardiquimod and inhibition with a specific antagonist 20S-protopanaxadiol (aPPD). The activation of lipid raft-associated TLR7 signaling was measured using western blotting, double immunohistochemistry and immunoprecipitation in liver tissues and HepG2 cells. TLR7 expression was up-regulated in human HCC tissues and hepatoma cell line. Proliferation and migration of HepG2 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 inhibition using aPPD significantly reduced HepG2 cell migration in vitro. The lipid raft protein caveolin-1 and flotillin-1 were involved with enhanced TLR7 signaling in HCC.
  
  
  CONCLUSIONS
  The data suggest that inhibiting TLR7 with antagonists, like aPPD, could potentially be used as a novel therapeutic approach for HCC.
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Yuan
authors: Y
authors: Liu
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Xiaodong
authors: X
authors: Guo
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Liyuan
authors: L
authors: Wu
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Mei
authors: M
authors: Yang
authors: First Hepatobiliary Surgery Center, Beijing 302 Hospital, Beijing, China.
authors: Zhiwei
authors: Z
authors: Li
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Yinjie
authors: Y
authors: Gao
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Shuhong
authors: S
authors: Liu
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Guangde
authors: G
authors: Zhou
authors: Department of Pathology and Hepatology, Beijing 302 Hospital, Beijing, China.
authors: Jingmin
authors: J
authors: Zhao
mesh_terms: D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D051242:Caveolin 1 / Q000378:metabolism; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D007113:Immunity, Innate; D008024:Ligands; D008103:Liver Cirrhosis / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D021962:Membrane Microdomains / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D015398:Signal Transduction; D051199:Toll-Like Receptor 7 / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C495540:CAV1 protein, human; D051242:Caveolin 1; D008024:Ligands; D008565:Membrane Proteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; C106354:flotillins
keywords: TLR7; hepatocellular carcinoma; lipid rafts; migration; proliferation