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

  • Peiyao Zhu
  • Kun Zhou
  • Shilong Lu
  • Yu Bai
  • Ruiqun QiEmail author
  • Shuguang ZhangEmail author
Research Article

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.

Keywords

AHR COX2 ESCC PGE2 STAT3 

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

Notes

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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interests.

Ethical approval

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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Copyright information

© The International CCN Society 2020

Authors and Affiliations

  1. 1.Department of Thoracic SurgeryThe First Hospital of China Medical UniversityShenyangChina
  2. 2.Department of Otolaryngology, Dermatology, PathologyUniversity of Colorado Anschutz Medical CampusAuroraUSA
  3. 3.Department of DermatologyThe First Hospital of China Medical UniversityShenyangChina

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