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Int J Biol Sci 2023; 19(7):1983-2001. doi:10.7150/ijbs.81423 This issue Cite

Research Paper

Disruption of the tumor suppressor-like activity of aryl hydrocarbon receptor by arsenic in epithelial cells and human lung cancer

Yao Fu^1*, Zhuoyue Bi^1*, Haoyan Ji¹, Millie Elangbam¹, Qian Zhang², Yiran Qiu¹, Wenxuan Zhang¹, Chitra Thakur¹, Fei Chen^1✉

1. Stony Brook Cancer Center, Department of Pathology, Renaissance School of Medicine, Stony Brook University, Lauterbur Drive, Stony Brook, NY 11794, USA
2. Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201, USA
*Those two authors contributed equally to this manuscript.

✉ Corresponding author: Fei.Chen.1edu

Abstract

As the most classic and extensively studied transcription factor in response to environmental toxic chemicals, the human aryl hydrocarbon receptor (AHR) has been implicated in mediating some oncogenic responses also. Limited information is available, however, on whether arsenic, a widely presented environmental carcinogen, can regulate AHR to exert its carcinogenic activity. Through chromatin immunoprecipitation and sequencing (ChIP-seq), CRISPR-Cas9 gene editing, RNA-seq, and immunohistochemistry (IHC), in this report we provided evidence showing that arsenic enforces TGFβ and other oncogenic signaling pathways in bronchial epithelial cells through disrupting the tumor suppressor-like activity of AHR. AHR is normally enriched on a number of oncogenic genes in addition to the known phase I/II enzymes, such as genes in TGFβ and Nrf2 signaling pathways and several known oncogenes. Arsenic treatment substantially reduced the binding of AHR on these genes followed by an increased expression of these genes. CRISPR-Cas9-based knockout of AHR followed by RNA-seq further demonstrated increased expression of the TGFβ signaling and some oncogenic signaling pathway genes in the AHR knockout cells. IHC studies on human tissue samples revealed that normal human lung tissues expressed high level of AHR. In contrast, the AHR expression was diminished in the lung cancer tissues. Accordingly, the data from this study suggest that AHR has tumor suppressor-like activity for human lung cancer, and one of the carcinogenic mechanisms of arsenic is likely mediated by the inhibition of arsenic on the tumor suppressor-like activity of AHR.

Keywords: Arsenic, AHR, tumor suppressor, TGFβ, lung cancer

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