Altered expression of E-cadherin in hepatocellular carcinoma: Correlations with genetic alterations, β-catenin expression, and clinical features

Abstract

H epatocellular carcinoma (HCC) is one of the most common malignancies and a leading cause of death by cancer worldwide. Epidemiologic studies have shown that more than 70% of HCC cases are linked to chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). Other risk factors include alcohol-related cirrhosis, dietary intake of aflatoxin B1 in some tropical areas, and inherited metabolic disorders such as tyrosinemia, hemochromatosis, and ␣1-antitrypsin deficiency. Recent insights into the mechanisms underlying HCC development have been provided by genome-wide allelotype studies and comparative genomic hybridization, showing numerous chromosomal changes during tumor development and progression. 1-5 These studies have led to the identification of a number of host factors as culprits in liver malignancy. Notably, allelic imbalance at chromosome 17p13 and frequent mutations of the p53 gene have been correlated with exposure to aflatoxin B1 and chronic HBV infection. 3 Mutations of ␤-catenin or its binding partner axin1, leading to abnormal activation of the Wnt pathway, have been implicated in about one third of HCC cases. 6,7 Among other common alterations, the long arm of chromosome 16 is a region of frequent loss of heterozygosity (LOH) in HCC, with deletion rates ranging from 28% to 70% in different studies. [8][9][10][11] This chromosomal arm carries a cluster of cadherin genes located at 16q22.1, and it has been proposed that deregulation of E-cadherin might be involved in liver carcinogenesis. [12][13][14][15]

Altered Distribution and Expression Pattern of E-cadherin in Hepatocellular Carcinomas: Correlations with Prognosis and Clinical Features

“…Immunohistochemical analysis of E-cadherin expression in TMA including 125 HCCs tissues revealed obvious variations among tumor samples, ranging from complete or heterogeneous downregulation in 42.4% of cases to striking overexpression in 34.4% of tumors, which was similar to the results of Buendia's (Wei et al, 2002), and E-cadherin level in cytoplasm was not associated with OS too. Different from the membrane and cytoplasm alone, we considered both factors in coming and found the high membrane/ cytoplasm ratio was an independence prognostic factor.…”

“…It has been reported that liver metastases of gastric tumors are composed strongly E-cadherin-positive cells during outgrowth in the liver environment (Mayer et al, 1993). E-cadhrin can also promote lymphovascular and intraepithelial invasion in other tumor types, enforced intercellular adhesion mediated by E-cadherin might favor the intake and expansion of tumor cells in liver and the shift of E-cadherin between membrane and cytoplasm may be associated with metabolite and functional changes of E-cadherin (Wei et al, 2002). To gain further insight into E-cadherin involvement of in HCC, we use immunohistochemistry to examine the levels of E-cadherin expression in 125 primary HCC samples.…”

Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma

“…In addition, an inverse correlation between E-cadherin expression and Snail expression had been found in a previous study using HCC cell lines; however, no association was found between the two gene expressions in the 47 HCC and eight NIN tissue samples in this study. Several reports have shown two mechanisms in the downregulation of E-cadherin in HCC; one is the hypermethylation of the E-cadherin promoter and the other is the loss of heterozygosity of the E-cadherin gene (Kanai et al, 1997;Matsumura et al, 2001;Wei et al, 2002). The authors demonstrated that DNA hypermethylation of the Ecadherin promoter region was observed in 33 -67% and loss of heterozygosity (LOH) was detected in 30 -43% of HCC tissues.…”

Downregulation of E-cadherin by hepatitis B virus X antigen in hepatocellullar carcinoma

“…Downregulated expression of E-cadherin is common in HCC, with promoter methylation observed early in hepatocarcinogenesis, while LOH of the E-cadherin locus is common during tumor progression (Kanai et al, 1997(Kanai et al, , 2000. The findings that downregulation of E-cadherin is associated with chronic HBV infection (Wei et al, 2002), that HBxAg promotes cell migration (Lara-Pezzi et al, 2001a, b) and reduces cell adhesion (Lian et al, 2003), suggest that HBxAg may downregulate E-cadherin. The inverse correlation between HBxAg and E-cadherin in tissue culture cells (Figure 2) and in tumor/nontumor tissues (Figure 3), and that HBxAg promotes E-cadherin promoter methylation (Figure 4), support the hypothesis that HBxAg targets E-cadherin.…”

“…A major E-cadherin-binding protein, b-catenin, plays a critical role in Wnt signaling and in tumorigenesis (Wei et al, 2002). E-cadherin-binding sequesters b-catenin to the cell membrane, where b-catenin signaling is inhibited (Gottardi et al, 2001).…”