title: Effect of toll-like receptor 7 and 9 targeted therapy to prevent the development of hepatocellular carcinoma.
abstract: OBJECTIVE
  Chronic liver disease is a predisposing factor for development of hepatocellular carcinoma (HCC). Toll-like receptors play a crucial role in immunity against microbial pathogens and recent evidence suggests that they may also be important in pathogenesis of chronic liver disease. The purpose of this study was to determine whether TLR7 and TLR9 are potential targets for prevention and progression of HCC.
  
  
  METHODS
  Tissue microarrays containing liver samples from patients with cirrhosis, viral hepatitis and HCC were examined for expression of TLR7 and TLR9 and the data obtained was validated in liver specimens from the hospital archives. Proliferation of human HCC cell lines was studied following stimulation of TLR7 and TLR9 using agonists (imiquimod and CpG-ODN respectively) and inhibition with a specific antagonist (IRS-954) or chloroquine. The effect of these interventions was confirmed in a xenograft model and diethylnitrosamine (DEN)/nitrosomorpholine (NMOR)-induced model of HCC.
  
  
  RESULTS
  TLR7 and TLR9 expression was up-regulated in human HCC tissue. Proliferation of HuH7 cells in vitro increased significantly in response to stimulation of TLR7. TLR7 and TLR9 inhibition using IRS-954 or chloroquine significantly reduced HuH7 cell proliferation in vitro and inhibited tumour growth in the mouse xenograft model. HCC development in the DEN/NMOR rat model was also significantly inhibited by chloroquine (P < 0.001).
  
  
  CONCLUSIONS
  The data suggest that inhibiting TLR7 and TLR9 with IRS-954 or chloroquine could potentially be used as a novel therapeutic approach for preventing HCC development and/or progression in susceptible patients.
authors.affiliation: UCL Institute for Liver and Digestive Health, Royal Free Hospital, London, UK; Pathology Department, Minia University, El-Minia, Egypt.
authors.forename: Fatma E
authors.initials: FE
authors.lastname: Mohamed
authors.forename: Rajai M
authors.initials: RM
authors.lastname: Al-Jehani
authors.forename: Shane S
authors.initials: SS
authors.lastname: Minogue
authors.forename: Fausto
authors.initials: F
authors.lastname: Andreola
authors.forename: Alison
authors.initials: A
authors.lastname: Winstanley
authors.forename: Steven W M
authors.initials: SW
authors.lastname: Olde Damink
authors.forename: Abeba
authors.initials: A
authors.lastname: Habtesion
authors.forename: Massimo
authors.initials: M
authors.lastname: Malagó
authors.forename: Nathan
authors.initials: N
authors.lastname: Davies
authors.forename: Tu Vinh
authors.initials: TV
authors.lastname: Luong
authors.forename: Amar P
authors.initials: AP
authors.lastname: Dhillon
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.forename: Dipok K
authors.initials: DK
authors.lastname: Dhar
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000517:prevention & control; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology / Q000627:therapeutic use; D004247:DNA / Q000494:pharmacology / Q000627:therapeutic use; D056945:Hep G2 Cells; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000517:prevention & control; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D011916:Rats, Inbred F344; D046888:Tissue Array Analysis; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C526793:IRS 954; D019394:Ki-67 Antigen; D016328:NF-kappa B; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D042461:Vascular Endothelial Growth Factor A; D002738:Chloroquine; D004247:DNA; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; CpG-ODN; DEN & NMOR; HCC; IRS; NF-kB; TLR; VEGF; chloroquine; imiquimod