Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis
Hepatic stellate cells promote intrahepatic cholangiocarcinoma progression via NR4A2/osteopontin/Wnt signaling axis
复制标题
肝星状细胞通过NR4A2/骨桥蛋白/Wnt信号轴促进肝内胆管癌进展
DOI：
10.1038/s41388-021-01705-9
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发表时间：
2021-03-19
期刊：
影响因子：
8
通讯作者：
Qiu, Shuang-Jian
中科院分区：
文献类型：
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作者：
Jing, Chu-Yu;Fu, Yi-Peng;Qiu, Shuang-Jian
肝内胆管癌（ICC）是一种高度致命的恶性肿瘤，其特征是瘤内存在大量成纤维细胞。这些成纤维细胞可能与维持ICC的高侵袭性有关，而其促癌机制仍然很少报道。在这里，通过建立ICC细胞和肝星状细胞（HSC）的共培养模型，我们确定HSC触发核受体家族4亚组A成员2（NR 4A 2）的表达，该转录因子先前被报道为ICC细胞中炎症和癌症之间的分子开关。在功能上，NR 4A 2促进肿瘤增殖、转移潜力，并代表ICC患者总生存期的独立预后指标。从机制上讲，NR 4A 2通过转录激活上调骨桥蛋白（OPN）表达，从而增强Wnt/β-连环蛋白信号传导的活性。有趣的是，在共培养的背景下，血管内皮生长因子（VEGF），一种先前证明的NR 4A 2刺激物，不仅增强NR 4A 2表达，而且还可以通过NR 4A 2-OPN轴的干扰而减弱。综上所述，本研究提示NR 4A 2/OPN/Wnt信号轴是HSC促癌作用的关键执行者，而NR 4A 2/OPN/VEGF正反馈环可能有助于加强这种促癌作用。
Intrahepatic cholangiocarcinoma (ICC) is a highly fatal malignancy characterized by a vast amount of intra-tumoral fibroblasts. These fibroblasts are potentially implicated in maintaining the high aggressiveness of ICC, whereas its pro-cancer mechanisms remain scarcely reported. Here, by establishing co-culture models of ICC cells and hepatic stellate cells (HSCs), we identified that HSCs triggered the expression of nuclear receptor family 4 subgroup A member 2 (NR4A2), a transcription factor previously reported as a molecular switch between inflammation and cancer, in ICC cells. Functionally, NR4A2 promotes tumor proliferation, metastatic potentiality and represents an independent prognostic indicator for overall survival in ICC patients. Mechanistically, NR4A2 upregulates osteopontin (OPN) expression through transcriptional activation and thereby augments the activity of Wnt/β-catenin signaling. Intriguingly, in the context of co-culture, vascular endothelial growth factor (VEGF), a previously proved NR4A2 stimulus, not only enhances NR4A2 expression, but also can be blunted by the interference of the NR4A2-OPN axis. Altogether, this study suggests the NR4A2/OPN/Wnt signaling axis to be a pivotal executor of HSC-instigated cancer-promoting roles in ICC, and the NR4A2/OPN/VEGF positive feedback loop may help to reinforce the effect.