ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma
ID3 Promotes Stem Cell Features and Predicts Chemotherapeutic Response of Intrahepatic Cholangiocarcinoma
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ID3 促进干细胞特征并预测肝内胆管癌的化疗反应。
DOI：
10.1002/hep.30404
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发表时间：
2019-05-01
期刊：
影响因子：
13.5
通讯作者：
Xia, Qiang
中科院分区：
文献类型：
--
作者：
Huang, Lifeng;Cai, Jie;Xia, Qiang
癌症干细胞导致许多类型的癌症（包括肝内胆管癌（ICC））的高复发率和化疗耐药性。据报道，分化抑制剂 3 (ID3) 可促进癌症干细胞，但其在 ICC 中的作用尚不清楚。在这项研究中，我们发现与匹配的正常组织相比，ID3 在人 ICC 组织中高表达，并且与不良预后相关。功能研究表明，ID3 是体外和体内胆管癌干性维持所必需的。与 ID3 对癌症干细胞特征的调节一致，ID3 的转基因表达增强了胆管癌细胞的化疗耐药性。此外，我们发现ID3水平低的ICC患者从术后经动脉化疗栓塞中受益，而ID3水平高的患者则没有，这表明ID3在个体化ICC治疗中的重要性。从机制上讲，ID3 可以与 E47 相互作用并阻止 E47 募集到 β-catenin 启动子，从而导致 Wnt/β-catenin 信号传导激活。结论：我们的结果表明，ID3 可以通过增加 β-catenin 的转录活性来促进 ICC 的干性，并可以作为预测 ICC 患者对辅助化疗反应的生物标志物。
Cancer stem cells contribute to a high rate of recurrence and chemotherapeutic resistance in many types of cancer, including intrahepatic cholangiocarcinoma (ICC). Inhibitor of differentiation 3 (ID3) has been reported to promote cancer stem cells, but its role in ICC is obscure. In this study, we identified that ID3 is highly expressed in human ICC tissues compared with matched normal tissues and correlates with poor prognosis. Functional studies demonstrate that ID3 is required for stemness maintenance in cholangiocarcinoma both in vitro and in vivo. Consistent with the regulation of cancer stem cell features by ID3, transgenic expression of ID3 enhances chemoresistance of cholangiocarcinoma cells. Moreover, we found that ICC patients with low ID3 levels benefited from postoperative transarterial chemoembolization, whereas patients with high ID3 levels did not, indicating the significance of ID3 in individualized ICC therapy. Mechanistically, ID3 could interact with E47 and block E47 recruitment to the promoter of β‐catenin, which leads to activation of Wnt/β‐catenin signaling. Conclusion: Our results show that ID3 could promote the stemness of ICC by increasing the transcriptional activity of β‐catenin and could serve as a biomarker in predicting ICC patients’ response to adjuvant chemotherapeutics.