A lymphotoxin-driven pathway to hepatocellular carcinoma

Cancer Cell. 2009 Oct 6;16(4):295-308. doi: 10.1016/j.ccr.2009.08.021.

Abstract

Hepatitis B and C viruses (HBV and HCV) cause chronic hepatitis and hepatocellular carcinoma (HCC) by poorly understood mechanisms. We show that cytokines lymphotoxin (LT) alpha and beta and their receptor (LTbetaR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTalphabeta expression in mice induces liver inflammation and HCC, causally linking hepatic LT overexpression to hepatitis and HCC. Development of HCC, composed in part of A6(+) oval cells, depends on lymphocytes and IKappa B kinase beta expressed by hepatocytes but is independent of TNFR1. In vivo LTbetaR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTbetaR inhibition in LTalphabeta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / virology
  • Case-Control Studies
  • Cell Transformation, Viral
  • Chemokines / metabolism
  • Chromosome Aberrations
  • Gene Expression Regulation, Neoplastic
  • Hepatitis B, Chronic / immunology*
  • Hepatitis C, Chronic / immunology*
  • Hepatocytes / immunology
  • Hepatocytes / virology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • Ligands
  • Liver / immunology*
  • Liver / virology
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / virology
  • Lymphocytes / immunology*
  • Lymphocytes / virology
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / metabolism*
  • Lymphotoxin-alpha / genetics
  • Lymphotoxin-alpha / metabolism*
  • Lymphotoxin-beta / genetics
  • Lymphotoxin-beta / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor, Type I / genetics
  • Receptors, Tumor Necrosis Factor, Type I / metabolism
  • Receptors, Tumor Necrosis Factor, Type II / genetics
  • Receptors, Tumor Necrosis Factor, Type II / metabolism
  • Recombinant Proteins / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor Ligand Superfamily Member 14 / metabolism
  • Tumor Necrosis Factor-alpha / metabolism
  • Up-Regulation

Substances

  • Biomarkers, Tumor
  • Chemokines
  • Homeodomain Proteins
  • LTB protein, human
  • LTBR protein, human
  • Ligands
  • Ltb protein, mouse
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • Lymphotoxin-beta
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor, Type I
  • Receptors, Tumor Necrosis Factor, Type II
  • Recombinant Proteins
  • TNFSF14 protein, human
  • Tnfrsf1a protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 14
  • Tumor Necrosis Factor-alpha
  • RAG-1 protein
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse

Associated data

  • GEO/GSE14467