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.
Wei
Yu
Y
Unité de Recombinaison et Expression Génétique (Inserm U163), Institut Pasteur, Paris, France.
Van Nhieu
Jeanne Tran
JT
Prigent
Sylvie
S
Srivatanakul
Petcharin
P
Tiollais
Pierre
P
Buendia
Marie-Annick
MA
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