TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF family whose transcripts are expressed in various human tissues. Since TWEAK has a variety of biological activities, we investigated TWEAK sensitivity, expression, and physiological role in human hepatocellular carcinomas (HCCs). Tweak receptor was detected in four kinds of HCC cells. TWEAK significantly promoted cell proliferation and induced nuclear factor-kappaB activation in all HCC cells. Surprisingly, we found that HCC cells constitutively express TWEAK. In addition, soluble TWEAK was detected in culture medium. We found that TWEAK also promotes cell proliferation and induces the secretion of IL-8 and MCP-1 in human umbilical vein endothelial cell. Finally, culture medium from Sh-Hep1 cells incubated with anti-TWEAK antibody significantly inhibited endothelial cell tube formation. In conclusion, these results indicate that TWEAK might play a critical role in HCC cellular proliferation using both autocrine and paracrine mechanisms, and modulate tumor-related angiogenesis. (C) 2004 Elsevier Inc. All rights reserved.