A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma

作者：Haybaeck Johannes; Zeller Nicolas; Wolf Monika Julia; Weber Achim; Wagner Ulrich; Kurrer Michael Odo; Bremer Juliane; Iezzi Giandomenica; Graf Rolf; Clavien Pierre Alain; Thimme Robert; Blum Hubert; Nedospasov Sergei A; Zatloukal Kurt; Ramzan Muhammad; Ciesek Sandra; Pietschmann Thomas; Marche Patrice N; Karin Michael; Kopf Manfred; Browning Jeffrey L; Aguzzi Adriano; Heikenwalder Mathias^*

来源：Cancer Cell, 2009, 16(4): 295-308.

DOI：10.1016/j.ccr.2009.08.021

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.

• 出版日期2009-10-6