Department of Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China.
School of Medicine, Nankai University, Tianjin, China.
Cancer Lett. 2019 May 28;450:132-143. doi: 10.1016/j.canlet.2019.02.040. Epub 2019 Mar 5.
Emerging evidence indicates that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence, and therapeutic resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying HCC CSC regulation remain largely unknown. Here we report our analysis of 97 paraffin-embedded HCC tumor specimens. We found that protein tyrosine kinase 2 (PTK2) expression correlated with liver CSC marker expression, overall survival, and recurrence-free survival in HCC patients. Our results further showed that PTK2 activated Wnt/β-catenin signaling by promoting nuclear accumulation of β-catenin in HCC cells. In this manner, PTK2 activates CSC traits and drives tumorigenicity in HCC cells, leading to HCC recurrence and sorafenib resistance. Moreover, PTK2 expression was negatively correlated with its level of promoter methylation. PTK2 apparently acts as an oncogene by increasing CSC traits and tumorigenicity in HCC. The present data suggest that PTK2 may be a novel prognostic biomarker for HCC recurrence, and a therapeutic target for HCC treatment.
新出现的证据表明，癌症干细胞（CSC）参与了肝癌（HCC）的肿瘤发生、肿瘤复发和治疗耐药。然而，HCC CSC 调控的机制在很大程度上仍不清楚。在这里，我们分析了 97 例石蜡包埋的 HCC 肿瘤标本。我们发现蛋白酪氨酸激酶 2（PTK2）的表达与 HCC 患者的肝 CSC 标志物表达、总生存率和无复发生存率相关。我们的结果进一步表明，PTK2 通过促进 HCC 细胞中β-连环蛋白的核积累来激活 Wnt/β-连环蛋白信号通路。通过这种方式，PTK2 激活了 CSC 特征，并驱动 HCC 细胞的致瘤性，导致 HCC 复发和索拉非尼耐药。此外，PTK2 的表达与启动子甲基化水平呈负相关。PTK2 通过增加 HCC 中的 CSC 特征和致瘤性，显然发挥了癌基因的作用。本研究数据表明，PTK2 可能是 HCC 复发的一个新的预后生物标志物，也是 HCC 治疗的一个潜在治疗靶点。
