PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling
PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling
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PTK2通过激活Wnt/β-连环蛋白信号传导促进肝细胞癌中的癌症干细胞特征
DOI：
10.1016/j.canlet.2019.02.040
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Xu, Xiaojie
中科院分区：
文献类型：
--
作者：
Fan, Zhongyi;Duan, Jingjing;Xu, Xiaojie
越来越多的证据表明，癌症干细胞（CSCs）参与了肝细胞癌（HCC）的肿瘤发生、肿瘤复发和治疗耐药性。然而，HCC CSC调控的潜在机制在很大程度上仍然未知。在这里，我们报告我们的分析97石蜡包埋肝癌肿瘤标本。我们发现，蛋白酪氨酸激酶2（PTK 2）表达与肝CSC标志物表达，总生存率和HCC患者的无复发生存率相关。我们的研究结果进一步表明，PTK 2通过促进HCC细胞中β-catenin的核积累来激活Wnt/β-catenin信号传导。以这种方式，PTK 2激活CSC性状并驱动HCC细胞中的致瘤性，导致HCC复发和索拉非尼耐药。PTK 2的表达与其启动子甲基化水平呈负相关。PTK 2通过增加CSC特征和HCC中的致瘤性而明显地作为癌基因起作用。目前的数据表明，PTK 2可能是HCC复发的新的预后生物标志物，以及HCC治疗的治疗靶点。
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/beta-catenin signaling by promoting nuclear accumulation of beta-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.