Targeting Wnt/β-catenin pathway in hepatocellular carcinoma treatment

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Liver cancer is generally related to hepatitis B or C infection and cirrhosis. Usually, patients with HCC are asymptomatic and are diagnosed at late stages when surgical treatment is no longer suitable. Limited treatment options for patients with advanced HCC are a major concern. Therefore, there is an urge for finding novel therapies to treat HCC. Liver cancer is highly heterogeneous and involved deregulation of several signaling pathways. Wnt/β-catenin pathway is frequently upregulated in HCC and it is implicated in maintenance of tumor initiating cells, drug resistance, tumor progression, and metastasis. A great effort in developing selective drugs to target components of the β-catenin pathway with anticancer activity is underway but only a few of them have reached phase I clinical trials. We aim to review the role of β-catenin pathway on hepatocarcinogenesis and liver cancer stem cell maintenance. We also evaluated the use of small molecules targeting the Wnt/β-catenin pathway with potential application for treatment of HCC.

Keywords: Hepatocellular carcinoma; Liver cancer stem cells; Molecular therapy; Wnt/β-catenin pathway.

Figure 1

Wnt-β-catenin signaling pathway. Binding of Wnt protein initiates a cascade, which results in activation of β-catenin, its accumulation in the cytoplasm and translocation into the nucleus to enhance the transcription of target genes (Left); When Fz/LRP receptors are not engaged, CK1 and GSK3B sequentially phosphorylate Axin-bound β-catenin. Consequently, β-catenin is ubiquitinated and targeted for rapid destruction by the proteasome (Right).

Figure 2

Synergistic inhibition of proliferation of liver cancer stem cells targeting β-catenin and Ras/Raf/MAPK pathways. FH535 and Sorafenib combination on inhibition of [³H]-Thymidine incorporation in liver cancer stem cells (CD133⁺, CD44⁺ and CD24⁺) Calculated combination index (CI) of less than 1. From Galuppo et al[12] with permission of Anticancer Research.