[Frontiers in Bioscience 11, 1901-1915, May 1, 2006]

Wnt/frizzled signaling in hepatocellular carcinoma

Han Chu Lee, Miran Kim, and Jack R. Wands

The Liver Research Center and Department of Medicine, Rhode Island Hospital and Brown Medical School, Providence, Rhode Island 02903 U.S.A.


1. Abstract
2. Overview of the Wnt/FZD signaling
2.1. Wnt ligands and their receptors
2.2. Canonical Wnt/FZD signaling
2.3. Non-canonical Wnt/FZD signaling
3. Alterations of the canonical Wnt/FZD signaling pathway in hepatocellular carcinoma
3.1. Wnt ligands and their regulatory proteins
3.2. FZDs
3.3. LRP5/6 and Dkk
3.4. Dsh
3.5. Beta-catenin
3.6. APC
3.7. Axin/Conductin
3.8. GSK-3beta
3.9. LEF/TCFs
3.10. Target genes
4. Conclusions and perspectives
5. Acknowledgments
6. References


The Wnt/Frizzled (FZD) signaling cascade is important for cell fate determination during embryonic development as well as maintaining tissue homeostasis in the adult. In addition to these physiologic roles, studies have shown that deregulation of Wnt/FZD signaling occurs during carcinogenesis. As an example, over 90% of the colorectal cancers have mutations in adenomatous polyposis coli (APC) or beta-catenin genes. In addition, hepatocellular carcinoma (HCC) is another tumor with frequent aberrant activation of beta-catenin signaling. Nuclear and/or cellular beta-catenin accumulation, a hallmark of the activated canonical Wnt/FZD signaling, has been observed in 33-67% of tumors. However, mutations of APC and/or beta-catenin genes are found only in about 20-30% of HCCs, suggesting that the predominant mechanism(s) activating Wnt/FZD signaling pathway may be different from that found in colorectal cancers. There is accumulating evidence to suggest that regulatory mechanisms other than mutations involving beta-catenin or proteins in its destruction complex, many of which involve upstream components of the Wnt/FZD cascade, are important in HCC. Furthermore, information on the target genes of Wnt/FZD signaling and their roles in hepatocarcinogenesis is limited despite the recent discovery of several candidate genes. This review focuses on the alterations of Wnt/FZD signaling pathways and their relationship to the pathogenesis of HCC. A better understanding of the precise mechanisms of altered Wnt/FZD signaling may provide new molecular targets for therapy of HCC.