Anti-apoptotic N-cadherin signaling and its prognostic implication in human hepatocellular carcinomas.
N-cadherin signaling has recently been implicated in the progression of certain epithelial tumors by promoting invasion and dissemination of cancer cells. N-cadherin has also been reported to exert an anti-apoptotic effect. In this study, we attempted to evaluate the participation of this adhesion molecule in the progression of human hepatocellular carcinomas (HCCs) by analyzing its anti-apoptotic signaling as well as its prognostic implication in HCC patients. N-cadherin was found to be expressed in human HCCs. We established a stable human HCC cell line expressing a truncated N-cadherin, NCaddeltaC, with a dominant-negative action. NCaddeltaC-expressing cells were more susceptible to bile acid-induced apoptosis than control cells. N-cadherin was found to complex with procaspase-8, and this association was diminished in NCaddeltaC-expressing cells, leading to enhanced procaspase-8 recruitment to death-inducing signaling complex following bile acid treatment. A clinicopathological analysis in patients who had undergone surgical resection for HCC revealed that tumoral N-cadherin up-regulation was significantly related to poor recurrence-free and overall survival. Our findings implicate N-cadherin signaling as contributing to HCC progression by exerting anti-apoptotic effects. Thus, we suggest that the selective interruption of this signaling may have therapeutic potential.
Gwak
Geum-Youn
GY
Department of Internal Medicine, Seoul National University College of Medicine, Chongno-gu, Seoul, Republic of Korea.
Yoon
Jung-Hwan
JH
Yu
Su Jong
SJ
Park
Su Cheol
SC
Jang
Ja June
JJ
Lee
Kyoung Bun
KB
Lee
Sung-Hee
SH
Lee
Soo-Mi
SM
Shin
Chan Soo
CS
Suh
Kyung-Suk
KS
Lee
Hyo-Suk
HS
D017209:Apoptosis; D001647:Bile Acids and Salts / Q000494:pharmacology; D014408:Biomarkers, Tumor; D015820:Cadherins / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000175:diagnosis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000378:metabolism / Q000601:surgery; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies
D001647:Bile Acids and Salts; D014408:Biomarkers, Tumor; D015820:Cadherins; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases