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.
Department of Pathology, University Hospital Zurich, CH 8091 Zurich, Switzerland.
Johannes
J
Haybaeck
Nicolas
N
Zeller
Monika Julia
MJ
Wolf
Achim
A
Weber
Ulrich
U
Wagner
Michael Odo
MO
Kurrer
Juliane
J
Bremer
Giandomenica
G
Iezzi
Rolf
R
Graf
Pierre-Alain
PA
Clavien
Robert
R
Thimme
Hubert
H
Blum
Sergei A
SA
Nedospasov
Kurt
K
Zatloukal
Muhammad
M
Ramzan
Sandra
S
Ciesek
Thomas
T
Pietschmann
Patrice N
PN
Marche
Michael
M
Karin
Manfred
M
Kopf
Jeffrey L
JL
Browning
Adriano
A
Aguzzi
Mathias
M
Heikenwalder
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