Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China; Department of Immunology, Fourth Military Medical University, Xi'an, 710032, China.
Department of Pulmonary Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
Exp Cell Res. 2020 Nov 1;396(1):112288. doi: 10.1016/j.yexcr.2020.112288. Epub 2020 Sep 14.
Cancer stem cells (CSCs) play an important role in shaping the invasive cancer phenotype by contributing to tumor initiation, metastasis, relapse, and therapeutic resistance in non-small cell lung cancer (NSCLC). The Aryl hydrocarbon receptor (AhR), a ligand activated transcription factor, which is well known for mediating the toxicity and tumorigenesis of a variety of environmental pollutants, has been extensively recognized as an important mediator in NSCLC development. Here, evidence showed that AhR was overexpressed in NSCLC tissues, and a high AhR protein level was associated with an aggressive tumor phenotype. Knockdown of AhR suppressed cell proliferation, invasion and migration, as well as CSC-like properties, while upregulation and activation of AhR enhanced CSC-like properties and increased stem cell-associated gene expression in NSCLC cells. Elevated and activated AhR leads to phosphorylation of janus kinase 2 (Jak2), as well as its downstream effector, activator of transcription 3 (STAT3), while inhibition of Jak2/STAT3 signaling by pharmacologic approach attenuates the effects of AhR-mediated NSCLC cell stemness, suggesting a role for the Jak2/STAT3 pathway in AhR-regulated NSCLC stemness. In summary, our study uncovers a transcriptional-independent mechanism of AhR through which AhR mediates NSCLC stemness via Jak2/STAT3 signaling pathway, indicating a promising target for the treatment of NSCLC.
癌症干细胞 (CSCs) 通过促进非小细胞肺癌 (NSCLC) 的肿瘤起始、转移、复发和治疗抵抗，在塑造侵袭性癌症表型方面发挥着重要作用。芳香烃受体 (AhR) 是一种配体激活的转录因子，它以介导多种环境污染物的毒性和肿瘤发生而闻名，已被广泛认为是 NSCLC 发展的重要介质。在这里，有证据表明 AhR 在 NSCLC 组织中过度表达，并且 AhR 蛋白水平高与侵袭性肿瘤表型相关。AhR 的敲低抑制了细胞增殖、侵袭和迁移以及 CSC 样特性，而 AhR 的上调和激活增强了 CSC 样特性，并增加了 NSCLC 细胞中与干细胞相关的基因表达。升高和激活的 AhR 导致 Janus 激酶 2 (Jak2) 及其下游效应物转录激活因子 3 (STAT3) 的磷酸化，而通过药理学方法抑制 Jak2/STAT3 信号通路减弱了 AhR 介导的 NSCLC 细胞干性的作用，表明 Jak2/STAT3 通路在 AhR 调节的 NSCLC 干性中起作用。总之，我们的研究揭示了 AhR 的一种转录非依赖性机制，通过该机制，AhR 通过 Jak2/STAT3 信号通路介导 NSCLC 干性，表明这是治疗 NSCLC 的有希望的靶点。
