A review on the diagnosis and treatment of hepatocellular carcinoma with a focus on the role of Wnts and the dickkopf family of Wnt inhibitors

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide. There are multiple etiologic factors including viral and environmental influences that can lead to HCC. Successful screening for early HCC is challenging due to the lack of well characterized and specific biomarkers. However, achieving successful screening is critically important as early diagnosis can potentially provide curative opportunities. Once HCC is advanced, there are multiple therapeutic venues, but most eventually fail, therefore developing new targeted therapies may provide greater chance for effective therapies. Along these lines, the Wnt pathway has been identified as contributing to the development and progression of HCC. Wnts can modify HCC growth and invasive ability. A key factor in the Wnt pathway is the dickkopf (DKK) family of Wnt inhibitors. DKKs have also been shown to modulate HCC progression. Additionally, several studies have suggested that DKK expression in tissue and serum has diagnostic and prognostic value.

Keywords: DKK; beta-catenin; biomarker; hepatoma; morphogen.

Figure 1

Wnt signaling pathway. Notes: (A) In the absence of Wnts, β-catenin is ubiquitinated and targeted for degradation by a protein complex that consists of adenomatous polyposis coli, axin, and glycogen synthase kinase 3β. (B) Wnts bind their receptor complex, which may consist of several different proteins including frizzled, low-density lipoprotein receptor-related protein, and kremen. Activation of the receptor complex results in breakdown of the β-catenin degradation complex and accumulation of β-catenin which translocates to the nucleus and promotes transcription of target genes. Dickkopfs can block Wnt signaling through inhibiting low-density lipoprotein receptor-related protein activity. Abbreviations: APC, adenomatous polyposis coli; CK1a, casein kinase Ia; DKK, Dickkopf; DSH, disheveled; FZD, frizzled; GSK3β, glycogen synthase kinase 3β; LRP, low-density lipoprotein receptor-related protein; P, phosphate; TCF/LEF, T-cell factor/lymphoid-enhancing factor.