Altered expression of E-cadherin in hepatocellular carcinoma: correlations with genetic alterations, beta-catenin expression, and clinical features.
E-cadherin is a key cell adhesion protein implicated as a tumor/invasion suppressor in human carcinomas and a binding partner of beta-catenin, which plays a critical role in Wnt signaling and in tumorigenesis. Here we report genetic and expression studies of E-cadherin and beta-catenin in hepatocellular carcinoma (HCC). Immunohistochemical analysis of E-cadherin expression in 37 HCCs and adjacent nontumor tissues revealed important variations among tumor samples, ranging from complete or heterogeneous down-regulation in 35% of cases to marked overexpression in 40% of tumors. Loss of E-cadherin expression was closely associated with loss of heterozygosity (LOH) at the E-cadherin locus and methylation of CpG islands in the promoter region (P <.002), predominantly in hepatitis B virus (HBV)-related tumors (P <.005). No mutation of the E-cadherin gene could be detected in the tumors examined, suggesting the requirement for reversible mechanisms of E-cadherin down-regulation. In most HCCs, including E-cadherin-positive and -negative cases, beta-catenin was strongly expressed at the cell membrane and nuclear accumulation of the protein was correlated with the presence of mutations in the beta-catenin gene itself, but not with E-cadherin loss. At difference with a number of epithelial cancers, vascular invasion was frequently noted in HCCs showing enforced expression of the membranous E-cadherin/beta-catenin complex. In conclusion, these data support the notion that E-cadherin might play diverse and seemingly paradoxic roles in HCC, reflecting specific requirements for tumor growth and spread in the liver environment.
Unité de Recombinaison et Expression Génétique (Inserm U163), Institut Pasteur, Paris, France.
Yu
Y
Wei
Jeanne Tran
JT
Van Nhieu
Sylvie
S
Prigent
Petcharin
P
Srivatanakul
Pierre
P
Tiollais
Marie-Annick
MA
Buendia
D000293:Adolescent; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000032:analysis / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002874:Chromosome Mapping; D002885:Chromosomes, Human, Pair 16; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics*; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic / Q000502:physiology; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin