Points of Therapeutic Intervention Along the Wnt Signaling Pathway in Hepatocellular Carcinoma

Sarah      B. Nambotin; Jack      R. Wands; Miran      Kim

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. However, there is little known about targeted therapeutics for the treatment of this devastating tumor. Among the growth factor signaling cascades deregulated in HCC, evidences suggest that the WNT/Frizzled – mediated signaling pathway plays a key role in the hepatic carcinogenesis. Aberrant activation of the signaling in HCC is mostly due to deregulated expression of the Wnt/β-catenin signaling components. This leads to the activation of the β-catenin/TCF dependent target genes, which controls cell proliferation, cell cycle, apoptosis or motility. It has been shown that disruption of the Wnt/β-catenin signaling cascade displayed anti-cancer properties in HCC. Currently, no therapeutic molecules targeting the WNT pathway are available or under clinical evaluation for the treatment of HCC. This review will discuss the identified potential molecular targets related to the canonical WNT signaling pathway and their potential therapeutic usefulness.

Keywords: β-catenin, frizzled, hepatocellular carcinoma, molecular target, targeted therapy, WNT, (WNT/FZD)-mediated signaling, The Canonical/-catenin Pathway, TCF/LEF, FZD7 receptor, catenin signaling, hepatitis/cirrhosis, iRNA-mediated, TCF-4 isoforms