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

Lei Yuan; Yumeng Zhang; Jianguo Xu; Feng Liu; Yingchao Liang; Beili Wang; Meihong Wu; Zhiyuan Fan; Liang Yang

doi:10.1016/j.isci.2025.112505

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

iScience. 2025 Apr 23;28(5):112505. doi: 10.1016/j.isci.2025.112505. eCollection 2025 May 16.

Authors

Lei Yuan¹, Yumeng Zhang², Jianguo Xu³, Feng Liu⁴, Yingchao Liang², Beili Wang², Meihong Wu⁵, Zhiyuan Fan⁶, Liang Yang^{1

2}

Affiliations

¹ Department of Hepatobiliary Surgery, Quzhou People's Hospital, 100 Minjiang Main Road, Quzhou, Zhejiang 324000, China.
² Department of Radiation Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.
³ Department of Plastic Surgery, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
⁴ Department of Scientific Research, Novel-Intel Biotech (Nanjing) Co., Ltd, Nanjing 211899, China.
⁵ Department of Oncology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
⁶ Department of Breast Surgery, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 201204, China.

Abstract

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 in vitro and in vivo. Mechanistically, AhR binds to the HEGBC 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 in vitro and in vivo. 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.

Keywords: biological sciences; cancer systems biology; health sciences; internal medicine; medical specialty; medicine; natural sciences; oncology; systems biology.