Dysregulated expression of dickkopfs for potential detection of hepatocellular carcinoma

Abstract

The prognosis for hepatocellular carcinoma (HCC) remains dismal due to the lack of diagnostic markers for early detection. This review will discuss the clinical potential of the dickkopf (DKK) family members as diagnostic and/or prognostic markers for HCC. In comparison to serum α-fetoprotein (AFP) level, which remains the gold standard for HCC diagnosis, high serum DKK1 levels have higher diagnostic value for HCC, especially for AFP-negative HCC, and can distinguish HCC from non-malignant chronic liver diseases. Additionally, the combination of serum DKK1 and AFP levels enhances diagnostic accuracy for HCC compared to serum DKK1 or AFP levels alone. Although DKK1 offers potential for its use in HCC diagnosis this review will discuss the challenges facing DKK1 and also shed some light on recent developments on the remaining DKK family members: DKK2, DKK3 and DKK4.

Keywords::

• AFP
• diagnosis
• dickkopfs
• hepatocellular carcinoma
• prognosis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Hepatocellular carcinoma (HCC) is a primary malignancy of liver cancer and is diagnosed late due to lack of sensitive diagnostic methods.

• The gold-standard marker for HCC diagnosis, α-fetoprotein (AFP), is also elevated in benign liver diseases and its sensitivity decreases with higher cutoff values.

• Wnt/β-catenin pathway is important for liver development, regeneration and preserves liver health. However, it is dysregulated in HCC.

• Dickkopfs (DKKs) (DKK1, DKK2, DKK3 and DKK4) are secreted glycoproteins that regulate Wnt/β-catenin signaling.

• Serum DKK1 levels are increased in HCC patients compared with healthy controls, chronic hepatitis patients and patients with liver cirrhosis. Compared with AFP, serum DKK1 is better able to distinguish HCC patients from hepatitis B virus and cirrhotic patients.

• Combined measurement of serum DKK1 and AFP enhances the diagnostic accuracy of HCC.

• The diagnostic accuracy of serum DKK1 in small (≤2 cm) HCC is not superior to AFP and also serum DKK1 levels need to be assessed in different etiologies of HCC, for example, hepatitis C virus-HCC, alcohol consumption.

• The diagnostic and prognostic potential of DKK2, DKK3 and DKK4 remains to be elucidated in HCC. However, DKK3 mRNA expression and serum levels have been associated with poor prognosis in various cancers including gastric, breast, and ovarian cancers.

Notes