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Modulation of aryl hydrocarbon receptor inhibits esophageal squamous cell carcinoma progression by repressing COX2/PGE2/STAT3 axis

  • RESEARCH ARTICLE
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Journal of Cell Communication and Signaling Aims and scope

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Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor prognosis. Aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor and emerging evidence shows it is associated with tumor initiation and promotion. However, the relationship between AHR and ESCC is not clear and it is meaningful to explore whether AHR could be a therapeutic target. In the present study, immunohistochemistry was performed to determine AHR expression levels in ESCC tissues. Knockdown of AHR expression in ESCC cell lines genetically and modulation of AHR by 3, 3′-diindolylmethane (DIM) pharmacologically both in vitro and in vivo were utilized to examine the corresponding alterations in cell growth, migration and invasion. Our study indicated that AHR expression levels were elevated in ESCC and associated with poor prognosis. Both knockdown and modulation of AHR inhibited tumor progression through down-regulating expression levels of PCNA, Bcl-2, Cyclin D1, MMP1, MMP2, MMP9 and up-regulating expression levels of Bax, Cleaved-Caspase 3. Our findings also indicated that repressing COX2/PGE2/STAT3 axis exerted inhibitory effects on ESCC both in vitro and in vivo assays. Taken together, AHR plays the key role in ESCC progression and targeting AHR as a therapeutic strategy with DIM is deserved for further exploration.

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Abbreviations

AHR:

Aryl hydrocarbon receptor

COX2:

Cyclooxygenase 2

CYP1A1:

Cytochrome P450, family 1, member A1

DIM:

3, 3′-diindolylmethane

ESCC:

Esophageal squamous cell carcinoma

OD:

Optical density

OS:

Overall survival

PCNA:

Proliferating cell nuclear antigen

PGE2 :

Prostaglandin E2

RSV:

Resveratrol

STAT3:

Signal transducer and activator of transcription 3

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Acknowledgments

This work was supported in part by a grant from Department of Education of Liaoning Province (LK201614). We thank the NHC Key Laboratory of Immunodermatology (China Medical University) for experiments carried out. We also thank Professor Ruiqun Qi for experimental instructions.

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Authors and Affiliations

  1. Department of Thoracic Surgery, The First Hospital of China Medical University, No.155 North Nanjing Street, Shenyang, 110001, China

    Peiyao Zhu, Kun Zhou, Yu Bai & Shuguang Zhang

  2. Department of Otolaryngology, Dermatology, Pathology, University of Colorado Anschutz Medical Campus, 12700 E 19th Avenue, Aurora, CO, 80045, USA

    Shilong Lu

  3. Department of Dermatology, The First Hospital of China Medical University, No.155 North Nanjing Street, Shenyang, 110001, China

    Ruiqun Qi

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  1. Peiyao Zhu
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  2. Kun Zhou
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Correspondence to Ruiqun Qi or Shuguang Zhang.

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All procedures performed in studies involving animals were in accordance with the ethical standards of the Animal Ethics and Experimental Committee of China Medical University (Approved number: 2018146).

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Zhu, P., Zhou, K., Lu, S. et al. Modulation of aryl hydrocarbon receptor inhibits esophageal squamous cell carcinoma progression by repressing COX2/PGE2/STAT3 axis. J. Cell Commun. Signal. 14, 175–192 (2020). https://doi.org/10.1007/s12079-019-00535-5

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