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Mol Cancer Res. 2016 Aug;14(8):696-706. doi: 10.1158/1541-7786.MCR-16-0069. Epub 2016 Apr 29.

Role for the Aryl Hydrocarbon Receptor and Diverse Ligands in Oral Squamous Cell Carcinoma Migration and Tumorigenesis.

Author information

1
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts.
2
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts. Boston University Molecular and Translational Medicine Program, Boston, Massachusetts.
3
Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, Massachusetts.
4
Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
5
Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts.
6
Integrative Physiology and Integrative Biology, Tufts University School of Medicine, Boston, Massachusetts.
7
Section of Computational Biomedicine, Department of Medicine, Boston University School of Medicine, Boston Massachusetts.
8
Department of Environmental Health, Boston University School of Public Health, Boston, Massachusetts. dsherr@bu.edu.

Abstract

Over 45,000 new cases of oral and pharyngeal cancers are diagnosed and account for over 8,000 deaths a year in the United States. An environmental chemical receptor, the aryl hydrocarbon receptor (AhR), has previously been implicated in oral squamous cell carcinoma (OSCC) initiation as well as in normal tissue-specific stem cell self-renewal. These previous studies inspired the hypothesis that the AhR plays a role in both the acquisition and progression of OSCC, as well as in the formation and maintenance of cancer stem-like cells. To test this hypothesis, AhR activity in two oral squamous cell lines was modulated with AhR prototypic, environmental and bacterial AhR ligands, AhR-specific inhibitors, and phenotypic, genomic and functional characteristics were evaluated. The data demonstrate that: (i) primary OSCC tissue expresses elevated levels of nuclear AhR as compared with normal tissue, (ii) AhR mRNA expression is upregulated in 320 primary OSCCs, (iii) AhR hyperactivation with several ligands, including environmental and bacterial ligands, significantly increases AhR activity, ALDH1 activity, and accelerates cell migration, (iv) AhR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, (v) AhR knockdown inhibits tumorsphere formation in low adherence conditions, and (vi) AhR knockdown inhibits tumor growth and increases overall survival in vivo These data demonstrate that the AhR plays an important role in development and progression of OSCC, and specifically cancer stem-like cells. Prototypic, environmental, and bacterial AhR ligands may exacerbate OSCC by enhancing expression of these properties.

IMPLICATIONS:

This study, for the first time, demonstrates the ability of diverse AhR ligands to regulate AhR activity in oral squamous cell carcinoma cells, as well as regulate several important characteristics of oral cancer stem cells, in vivo and in vitro Mol Cancer Res; 14(8); 696-706. ©2016 AACR.

PMID:
27130942
PMCID:
PMC4987205
DOI:
10.1158/1541-7786.MCR-16-0069
[Indexed for MEDLINE]
Free PMC Article

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