Solid evidence shows that tumor-initiating cells (T-ICs) are the root of tumor relapse and drug resistance, which lead to a poor prognosis in patients with hepatocellular carcinoma (HCC). Through an in vitro liver T-IC enrichment approach, we identified nuclear factor (erythroid-derived 2)-like 2 (NRF2) as a transcription regulator that is significantly activated in enriched liver T-IC populations. In human HCCs, NRF2 was found to be overexpressed, which was associated with poor patient survival. Through a lentiviral based knockdown approach, NRF2 was found to be critical for regulating liver T-IC properties, including self-renewal, tumorigenicity, drug resistance and expression of liver T-IC markers. Furthermore, we found that ROS-induced NRF2 activation regulates sorafenib resistance in HCC cells. Mechanistically, NRF2 was found to physically bind to the promoter of sonic hedgehog homolog (SHH), which triggers activation of the sonic hedgehog pathway. The effect of NRF2 knockdown was eliminated upon administration of recombinant SHH, demonstrating that NRF2 mediated T-IC function via upregulation of SHH expression. Our study suggests a novel regulatory mechanism for the canonical sonic hedgehog pathway that may function through the NRF2/SHH/GLI signaling axis, thus mediating T-IC phenotypes.

中文翻译：

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NRF2 / SHH信号级联促进肝细胞癌中的肿瘤起始细胞谱系和耐药性。

有确凿的证据表明，肿瘤起始细胞（T-ICs）是肿瘤复发和耐药性的根源，导致肝细胞癌（HCC）患者的预后不良。通过体外肝脏T-IC富集方法，我们鉴定了核因子（类胡萝卜素2）样2（NRF2）作为转录调节因子，在富集的肝脏T-IC人群中被显着激活。在人类肝癌中，发现NRF2过表达，这与患者存活不良有关。通过基于慢病毒的敲低方法，发现NRF2对于调节肝脏T-IC特性（包括自我更新，致瘤性，耐药性和肝脏T-IC标记的表达）至关重要。此外，我们发现ROS诱导的NRF2激活调节肝癌细胞中索拉非尼耐药性。机械上，NRF2被发现物理绑定到声波刺猬同源物（SHH）的启动子，从而触发声波刺猬通路的激活。施用重组SHH后，NRF2敲低的作用消除了，这表明NRF2通过上调SHH表达来介导T-IC功能。我们的研究表明，规范的声波刺猬通路可能通过NRF2 / SHH / GLI信号轴起作用，从而介导T-IC表型的新型调节机制。