Functional expression of TWEAK in human hepatocellular carcinoma: possible implication in cell proliferation and tumor angiogenesis.
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.
Kawakita
Tomoyuki
T
First Department of Internal Medicine, Mie University School of Medicine, Tsu, Mie 514-8507, Japan.
Shiraki
Katsuya
K
Yamanaka
Yutaka
Y
Yamaguchi
Yumi
Y
Saitou
Yukiko
Y
Enokimura
Naoyuki
N
Yamamoto
Norihiko
N
Okano
Hiroshi
H
Sugimoto
Kazushi
K
Murata
Kazumoto
K
Nakano
Takeshi
T
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D048069:Tumor Necrosis Factors
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D000074049:Cytokine TWEAK; D016328:NF-kappa B; D011994:Recombinant Proteins; C109743:TNFSF12 protein, human; D048069:Tumor Necrosis Factors