Department of Gastroenterology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan.
Int J Mol Sci. 2022 Mar 3;23(5):2801. doi: 10.3390/ijms23052801.
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.
癌症干细胞因其导致的恶性肿瘤和不良预后而受到关注。我们之前证明了肝干细胞样肝癌（HpSC-HCC）与高血管侵犯和不良预后相关。Dickkopf-1（DKK-1）是一种 Wnt 信号调节剂，在 HpSC-HCC 中高度表达。在这里，我们评估了血清 DKK-1 的诊断和预后潜力。与 205 例慢性肝病患者相比，391 例 HCC 患者的血清 DKK-1 水平明显升高。受试者工作特征曲线分析显示，DKK-1 诊断 HCC 和预测 3 年生存率的最佳截断值分别为 262.2 和 365.9 pg/mL。血清 DKK-1 水平高的 HCC 患者预后不良。我们评估了抗 DKK-1 抗体治疗对体内肿瘤生长的影响，以及重组 DKK-1 对体外细胞增殖、侵袭和血管生成的影响。DKK-1 敲低可降低癌细胞的增殖、迁移和侵袭。DKK-1 补充可促进体外血管生成；这种作用被抗 DKK-1 抗体所阻断。抗 DKK-1 抗体与 Huh7 细胞共注射可抑制其在 NOD/SCID 小鼠中的生长。因此，DKK-1 可促进 HCC 细胞的增殖、迁移和侵袭，并激活血管内皮细胞的血管生成。DKK-1 是 HCC 的预后生物标志物，也是靶向治疗的功能分子。
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