Exp Cell Res. 2020 Sep 14:112288. doi: 10.1016/j.yexcr.2020.112288. Online ahead of print.
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.