A Lymphotoxin-Driven Pathway to Hepatocellular Carcinoma

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• 作者：Johannes Haybaeck ; Nicolas Zeller ; Monika Julia Wolf ; Achim Weber ; Ulrich Wagner ; Michael Odo Kurrer ; Juliane Bremer ; Gi ; omenica Iezzi ; Rolf Graf ; Pierre-Alain Clavien ; Robert Thimme ; Hubert Blum ; Sergei A. Nedospasov ; Kurt Zatloukal ; Muhammad Ramzan ; S ; ra Ciesek ; Thomas Pietschmann ; Patrice N. Marc
• 刊名：Cancer Cell
• 出版年：2009
• 出版时间：6 October 2009
• 年：2009
• 卷：16
• 期：4
• 页码：295-308
• 全文大小：3231 K

文摘

Summary

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) α and β and their receptor (LTβR) are upregulated in HBV- or HCV-induced hepatitis and HCC. Liver-specific LTαβ 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 β expressed by hepatocytes but is independent of TNFR1. In vivo LTβR stimulation implicates hepatocytes as the major LT-responsive liver cells, and LTβR inhibition in LTαβ-transgenic mice with hepatitis suppresses HCC formation. Thus, sustained LT signaling represents a pathway involved in hepatitis-induced HCC.