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Abstract
BackgroundThere are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. Recent studies have identified the Frizzled-7 receptor (FZD7), important for activation of Wnt-mediated signaling, as a potential therapeutic target for HCC and other cancers.MethodsWe hypothesized that the extracellular domain of FZD7 (sFZD7) would be a clinically more relevant therapeutic modality than previously studied approaches to target FZD7. We expressed and purified sFZD7 from E. coli, and tested its functional activity to interact with Wnt3, its ability to inhibit Wnt3-mediated signaling, and its potential for combinatorial therapy in HCC.ResultssFZD7 pulled down Wnt3 from Huh7 cells, and decreased β-catenin/Tcf4 transcriptional activity in HCC cells. In vitro, sFZD7 dose-dependently decreased viability of three HCC cell lines (HepG2, Hep40, and Huh7, all with high FZD7 and Wnt3 mRNA), but had little effect on normal hepatocytes from three donors (all with low level FZD7 and Wnt3 mRNA). When combined with doxorubicin, sFZD7 enhanced the growth inhibitory effects of doxorubicin against HCC cells in vitro, and against Huh7 xenografts in vivo. Reduced expressions of c-Myc, cyclin D1, and survivin were observed in vitro and in vivo. Additionally, sFZD7 altered the levels of phosphorylated AKT and ERK1/2 induced by doxorubicin treatment in vitro, suggesting that several critical pathways are involved in the chemosensitizing effect of sFZD7.ConclusionsWe propose that sFZD7 is a feasible therapeutic agent with specific activity, which can potentially be combined with other chemotherapeutic agents for the improved management of HCC.
Highlights
There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide
Our study investigates a more readily translatable method to interfere with Frizzled-7 receptor (FZD7)/Wnt3 interaction, by using the extracellular peptide of FZD7 expressed and purified from E. coli to inhibit Wnt/b-catenin-mediated signaling in human HCC cell lines
We hypothesized that an extracellular domain peptide of FZD7 will be able to bind extracellular Wnt ligands, thereby reducing ligand interactions with FZD7 and inhibiting Wnt/b-catenin signaling in HCC
Summary
There are limited therapeutic options for hepatocellular carcinoma (HCC), the most common liver malignancy worldwide. The Wnt/b-catenin signaling pathway is commonly dysregulated in various cancers, including hepatocellular carcinoma (HCC) [1]. Aberrations in this pathway have been established to be critical contributors towards hepatocarcinogenesis [2]. Mutations of b-catenin are detected only in 20-30% of HCC [3,4,5,6,7]; and loss-of-function mutation of negative regulators axin and axin are rare in HCC [8,9,10] These observations suggest that other upstream elements may be important in the activation of FZDs are frequently upregulated in tumor cell lines and tissues [1]. Functional interaction between FZD7 and the Wnt ligand, leading to increased nuclear b-catenin accumulation, has been demonstrated in hepatitis B virus-induced HCC cells [12]
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