Polycyclic aromatic hydrocarbons promote tumorigenesis of gallbladder cancer via aryl hydrocarbon Receptor-HEGBC positive feedback axis

Gallbladder cancer (GBC) is a highly aggressive tumor associated with risk factors, such as chronic infection, gallstones, and exposure to harmful chemicals. Our study explores the role of polycyclic aromatic hydrocarbons (PAHs) and long noncoding RNA HEGBC in GBC progression. We found that PAHs activate the aryl hydrocarbon receptor (AhR), which enhances HEGBC expression and promotes GBC cell proliferation, invasion, and metastasis both <i>in vitro</i> and <i>in vivo</i>. Mechanistically, AhR binds to the <i>HEGBC</i> promoter, establishing a positive feedback loop that further activates AhR transcription. Moreover, CYP1A1 was identified as a key downstream effector of PAHs-AhR/HEGBC-mediated proliferation, migration, and invasion of GBC cells <i>in vitro</i> and <i>in vivo</i>. These findings provide the integrative view of a molecular mechanism loop for regulating the malignant progression of GBC centered by PAHs/AhR/HEGBC, which represents a promising strategy for the treatment of GBC.