Abstract
BackgroundHepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/β-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC.ResultsWe demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type β-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased β-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous β-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c-Myc, cyclin D1, and survivin expressions.ConclusionOur results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1.
Highlights
Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide
Over-expression of Wnt-1 protein in HCC tissue specimens and cell lines To confirm the expression of Wnt-1 protein in HCC, we used the anti-Wnt-1 antibody to detect its expression in seven pairs of HCC tissues and their corresponding adjacent non-tumor tissues
Our observations corroborate with published reports that Wnt-1 is upregulated in hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related HCC tissues and cell lines [16,19]
Summary
Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the primary form of human adult liver cancer. It is the fifth most common cancer worldwide, with about one million new cases diagnosed annually, and almost an equal number of deaths. It is predominant in China, most parts of South East Asia, and South Africa, where hepatitis B virus (HBV) infection is endemic [1]. 1025% of HCC patients are candidates for surgical resection and liver transplantation; the majority of patients have limited treatment options due to the lack of effective chemotherapy against this intrinsically resistant tumor [24]. New pharmacological interventions that offer even (page number not for citation purposes)
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