Clinical significance of target genes of Wnt/beta-catenin pathway in hepatocellular carcinoma

Abstract

BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and is particularly prevalent in Southeast Asia and China including Hong Kong. Wnt/beta-catenin pathway is one of the important signaling pathways and therapeutic target in liver cancer. In this study, we aimed to reveal the expression profile of these target genes and to investigate their clinicopathological significance in human HCC. MATERIAL AND METHODS: To elucidate the molecular mechanism of the deregulation of Wnt/beta-catenin pathway in HCC, we performed highthroughput quantitative RT-PCR analysis (Low Density Microarray, LDA) to study the gene expression patterns of Wnt-signaling molecules, include Wnt ligands, Fizzled receptor proteins, Wnt-related genes, on 38 pairs of human HCC samples and their corresponding non-tumourous livers. Ten target genes of Wnt/beta-catenin signaling were also evaluated, include c-myc, cyclinD1, LEF1, c-jun, Axin-2, VEGFA, DKK1, Frizzled 7, Twist1 and EGFR. RESULTS: LEF1 and DKK1 were found to be significantly overexpressed in human HCC (63% and 66%, respectively) when compared with their corresponding non-tumourous livers (P < 0.001 and P = 0.005, respectively). In addition, the expression level of LEF1 and DKK1 positively correlated with one another (P = 0.037). LEF1 was found to significantly correlate with venous invasion, absence of encapsulation and advanced tumour stage (P = 0.043, 0.008 and 0.045, respectively). The combination of LEF1 and DKK1 further increased their correlation with clinicopathological parameters in human HCC, like venous invasion and poorer cellular differentiation (Edmondson grading) (P = 0.021 and 0.047, respectively). CONCLUSIONS: Both LEF1 and DKK1 are upregulated in human HCC and associated with more aggressive tumour behaviour.