A lymphotoxin-driven pathway to hepatocellular carcinoma.
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.
Haybaeck
Johannes
J
Department of Pathology, University Hospital Zurich, CH 8091 Zurich, Switzerland.
Zeller
Nicolas
N
Wolf
Monika Julia
MJ
Weber
Achim
A
Wagner
Ulrich
U
Kurrer
Michael Odo
MO
Bremer
Juliane
J
Iezzi
Giandomenica
G
Graf
Rolf
R
Clavien
Pierre-Alain
PA
Thimme
Robert
R
Blum
Hubert
H
Nedospasov
Sergei A
SA
Zatloukal
Kurt
K
Ramzan
Muhammad
M
Ciesek
Sandra
S
Pietschmann
Thomas
T
Marche
Patrice N
PN
Karin
Michael
M
Kopf
Manfred
M
Browning
Jeffrey L
JL
Aguzzi
Adriano
A
Heikenwalder
Mathias
M
D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000821:virology; D016022:Case-Control Studies; D002472:Cell Transformation, Viral; D018925:Chemokines / Q000378:metabolism; D002869:Chromosome Aberrations; D015972:Gene Expression Regulation, Neoplastic; D019694:Hepatitis B, Chronic / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008099:Liver / Q000276:immunology* / Q000821:virology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology* / Q000821:virology; D008214:Lymphocytes / Q000276:immunology* / Q000821:virology; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000378:metabolism*; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D014408:Biomarkers, Tumor; D018925:Chemokines; D018398:Homeodomain Proteins; C505886:LTB protein, human; C505697:LTBR protein, human; D008024:Ligands; C505887:Ltb protein, mouse; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D053308:Lymphotoxin-beta; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; C505914:TNFSF14 protein, human; C506236:Tnfrsf1a protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; C064658:RAG-1 protein; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse