A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma

被引：329

作者：

Haybaeck, Johannes ^{[1
]}

Zeller, Nicolas ^{[1
]}

Wolf, Monika Julia ^{[1
]}

Weber, Achim ^{[2
,3
]}

Wagner, Ulrich ^{[4
]}

Kurrer, Michael Odo ^{[5
]}

Bremer, Juliane ^{[1
]}

Iezzi, Giandomenica ^{[6
]}

Graf, Rolf ^{[7
]}

Clavien, Pierre-Alain ^{[7
]}

Thimme, Robert ^{[8
]}

Blum, Hubert ^{[8
]}

Nedospasov, Sergei A. ^{[9
,10
]}

Zatloukal, Kurt ^{[11
]}

Ramzan, Muhammad ^{[12
,13
]}

Ciesek, Sandra ^{[14
,15
]}

Pietschmann, Thomas ^{[14
,15
]}

Marche, Patrice N. ^{[12
,13
]}

Karin, Michael ^{[16
,17
]}

Kopf, Manfred ^{[6
]}

Browning, Jeffrey L. ^{[18
]}

Aguzzi, Adriano ^{[1
]}

Heikenwalder, Mathias ^{[1
]}

机构：

[1] Univ Zurich Hosp, Dept Pathol, CH-8091 Zurich, Switzerland

[2] Univ Zurich Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland

[3] Univ Zurich Hosp, Inst Clin Pathol, CH-8091 Zurich, Switzerland

[4] Univ Zurich, Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland

[5] Cantonal Hosp Aarau, Dept Pathol, CH-5001 Aarau, Switzerland

[6] Swiss Fed Inst Technol, Inst Integrat Biol, CH-8952 Zurich, Schlieren, Switzerland

[7] Univ Zurich Hosp, Dept Surg, Swiss HPB Hepatopancreaticobiliary Ctr, CH-8091 Zurich, Switzerland

[8] Univ Freiburg, Dept Internal Med, D-79106 Freiburg, Germany

[9] VA Engelhardt Mol Biol Inst, Moscow 119991, Russia

[10] German Rheumatism Res Ctr, D-10117 Berlin, Germany

[11] Med Univ Graz, Inst Pathol, A-8036 Graz, Austria

[12] INSERM, F-38042 Grenoble, France

[13] Univ Grenoble 1, U823, Inst Albert Bonniot, F-38042 Grenoble, France

[14] Med Sch Hannover MHH, Ctr Expt & Clin Infect Res, TWINCORE, Div Expt Virol, D-30625 Hannover, Germany

[15] Helmholtz Ctr Infect Res HZI, D-30625 Hannover, Germany

[16] Univ Calif San Diego, La Jolla, CA 92093 USA

[17] Univ Calif Los Angeles, Los Angeles, CA 92093 USA

[18] Biogen Idec Inc, Dept Immunobiol, Cambridge, MA 02142 USA

来源：

CANCER CELL | 2009年 / 16卷 / 04期

基金：

瑞士国家科学基金会;

关键词：

VIRUS CORE PROTEIN; NF-KAPPA-B; BETA-RECEPTOR; SIGNAL PATHWAY; OVAL CELLS; EXPRESSION; LIVER; NECROSIS; PATHOGENESIS; CYTOKINE;

D O I：

10.1016/j.ccr.2009.08.021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 (LTOR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LT alpha beta 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 LT beta R stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTOR inhibition in LT alpha beta-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.

引用

页码：295 / 308

页数：14

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