title: Anti-apoptotic N-cadherin signaling and its prognostic implication in human hepatocellular carcinomas.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Chongno-gu, Seoul, Republic of Korea.
authors.forename: Geum-Youn
authors.initials: GY
authors.lastname: Gwak
authors.forename: Jung-Hwan
authors.initials: JH
authors.lastname: Yoon
authors.forename: Su Jong
authors.initials: SJ
authors.lastname: Yu
authors.forename: Su Cheol
authors.initials: SC
authors.lastname: Park
authors.forename: Ja June
authors.initials: JJ
authors.lastname: Jang
authors.forename: Kyoung Bun
authors.initials: KB
authors.lastname: Lee
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Lee
authors.forename: Soo-Mi
authors.initials: SM
authors.lastname: Lee
authors.forename: Chan Soo
authors.initials: CS
authors.lastname: Shin
authors.forename: Kyung-Suk
authors.initials: KS
authors.lastname: Suh
authors.forename: Hyo-Suk
authors.initials: HS
authors.lastname: Lee
mesh_terms: 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
chemical_list: D001647:Bile Acids and Salts; D014408:Biomarkers, Tumor; D015820:Cadherins; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases