AhR Promotes the Development of Non-small cell lung cancer by Inducing SLC7A11-dependent Antioxidant Function

Yuanhao Peng; Lianlian Ouyang; Yangying Zhou; Weiwei Lai; Yuanbing Chen; Zuli Wang; Bokang Yan; Zewen Zhang; Yanling Zhou; Xintong Peng; Jielin Chen; Xin Peng; Desheng Xiao; Shuang Liu; Yongguang Tao; Wenliang Liu

doi:10.7150/jca.82066

AhR Promotes the Development of Non-small cell lung cancer by Inducing SLC7A11-dependent Antioxidant Function

J Cancer. 2023 Mar 27;14(5):821-834. doi: 10.7150/jca.82066. eCollection 2023.

Authors

Yuanhao Peng^{1

2}, Lianlian Ouyang³, Yangying Zhou⁴, Weiwei Lai², Yuanbing Chen⁵, Zuli Wang⁶, Bokang Yan⁷, Zewen Zhang², Yanling Zhou⁴, Xintong Peng², Jielin Chen⁸, Xin Peng⁸, Desheng Xiao⁸, Shuang Liu⁴, Yongguang Tao^{1

2

8}, Wenliang Liu¹

Affiliations

¹ Department of Thoracic Surgery, Hunan Key Laboratory of Early Diagnosis and Precision Therapy in Lung Cancer, Second Xiangya Hospital, Central South University, Changsha, Hunan,410011, China.
² NHC Key Laboratory of Carcinogenesis, Cancer Research Institute and School of Basic Medicine, Central South University, Changsha, Hunan, 410078, China.
³ Department of dermatology, Second Xiangya Hospital, Central South University, Changsha,410011, China.
⁴ Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁵ Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁶ Center for Tissue Engineering and Stem Cell Research, Guizhou Medical University, Guizhou, 550025, China.
⁷ Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, Hunan, 412007, China.
⁸ Department of Pathology, School of Basic Medicine and Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.

Abstract

Objective: Aryl hydrocarbon receptor (AhR) is a transcription factor. It is reported that AhR is associated with non-small cell lung cancer (NSCLC), but the mechanisms underlying this relationship remain unclear. Therefore, we investigated the role of AhR in NSCLC to elucidate the underlying mechanisms. Methods: We collected clinical lung cancer samples and constructed AhR overexpression and knockdown cell lines to investigate the tumorigenicity of AhR in vivo and in vitro. Furthermore, we performed a ferroptosis induction experiment and chromatin immunoprecipitation experiment. Results: AhR was highly expressed in NSCLC tissue. AhR knockdown cells showed ferroptosis related phenomenon. Furthermore, Chromatin immunoprecipitation confirmed the correlation between AhR and solute carrier family 7 member 11 (SLC7A11) and ferroptosis induction experiment confirmed that AhR affects ferroptosis via SLC7A11. Specifically, AhR regulates ferroptosis-related SLC7A11, which affects ferroptosis and promotes NSCLC progression. Conclusions: AhR promoted NSCLC development and positively correlated with SLC7A11, affecting its actions. AhR bound to the promoter region of SLC7A11 promotes NSCLC by activating SLC7A11 expression, improving the oxidative sensitivity of cells, and inhibiting ferroptosis. Thus, AhR affects ferroptosis in NSCLC by regulating SLC7A11, providing foundational evidence for novel ferroptosis-related treatments.

Keywords: Ferroptosis; Receptors, aryl hydrocarbon; SLC7A11; non-small-cell lung cancer.