Abstract
Cancer stemness evinces interest owing to the resulting malignancy and poor prognosis. We previously demonstrated that hepatic stem cell-like hepatocellular carcinoma (HpSC-HCC) is associated with high vascular invasion and poor prognosis. Dickkopf-1 (DKK-1), a Wnt signaling regulator, is highly expressed in HpSC-HCC. Here, we assessed the diagnostic and prognostic potential of serum DKK-1. Its levels were significantly higher in 391 patients with HCC compared with 205 patients with chronic liver disease. Receiver operating characteristic curve analysis revealed the optimal cutoff value of DKK-1 to diagnose HCC and predict the 3-year survival as 262.2 and 365.9 pg/mL, respectively. HCC patients with high-serum DKK-1 levels showed poor prognosis. We evaluated the effects of anti-DKK-1 antibody treatment on tumor growth in vivo and of recombinant DKK-1 on cell proliferation, invasion, and angiogenesis in vitro. DKK-1 knockdown decreased cancer cell proliferation, migration, and invasion. DKK-1 supplementation promoted angiogenesis in vitro; this effect was abolished by an anti-DKK-1 antibody. Co-injection of the anti-DKK-1 antibody with Huh7 cells inhibited their growth in NOD/SCID mice. Thus, DKK-1 promotes proliferation, migration, and invasion of HCC cells and activates angiogenesis in vascular endothelial cells. DKK-1 is a prognostic biomarker for HCC and a functional molecule for targeted therapy.
Highlights
We previously demonstrated that hepatic stem cell markers, epithelial cell adhesion molecule (EpCAM), AFP, DKK-1, DLK1, CD133, and CK19, were upregulated in HpSC-hepatocellular carcinoma (HCC) compared with that in mature hepatocyteHCC (MH-HCC)
As EpCAM is a marker of liver cancer stem cells, we further evaluated the expression of genes encoding EpCAM and DKK-1 using EpCAM+/− cells sorted from Huh7 cells
To clarify whether the increase in serum DKK-1 levels could really be attributed to DKK-1 production in HCC cases with poor prognosis, we evaluated the expression of DKK-1 using immunohistochemistry (IHC) in 58 HCC samples obtained from patients who received surgery
Summary
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and occurs in people with chronic liver disease (CLD). It is the fourth leading cause of cancerrelated deaths worldwide [1]. GLOBOCAN data revealed that approximately 841,000 new cases of liver cancer and 782,000 related deaths were reported in 2018, which makes liver cancer the sixth most commonly diagnosed cancer [2]. The global incidence of HCC is heterogeneous due to the varying prevalence of the underlying risk factors. It has been estimated that 72% of the cases occur in Asia (>50% in China), 10% in Europe, 7.8% in Africa, 5.1% in North America, 4.6% in Latin America, and 0.5% in Oceania [3]. The incidence of HCC is presumed to increase over the 10–20 years, with
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