title: Role for the Aryl Hydrocarbon Receptor and Diverse Ligands In Oral Squamous Cell Carcinoma Migration and Tumorigenesis.
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: 1) primary OSCC tissue expresses elevated levels of nuclear AHR as compared to normal tissue, 2) Ahr mRNA expression is up-regulated in 320 primary OSCC, 3) AHR hyper-activation with several ligands, including environmental and bacterial ligands, significantly increases AHR activity, ALDH1 activity, and accelerates cell migration, 4) AHR inhibition blocks the rapid migration of OSCC cells and reduces cell chemoresistance, 5) AHR knockdown inhibits tumorsphere formation in low adherence conditions, and 6) 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.
  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.
authors.affiliation: Boston University School of Public Health, Department of Environmental Health, 72 E. Concord Street, Boston, MA 02118.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Stanford
authors.affiliation: Boston University School of Public Health, Department of Environmental Health, 72 E. Concord Street, Boston, MA 02118.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Ramirez-Cardenas
authors.affiliation: Boston University School of Public Health, Department of Environmental Health, 72 E. Concord Street, Boston, MA 02118.
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Boston University School of Public Health, Department of Environmental Health, 72 E. Concord Street, Boston, MA 02118.|Boston University Molecular and Translational Medicine Program, 72 E. Concord Street, Boston MA 02118.
authors.forename: Olga
authors.initials: O
authors.lastname: Novikov
authors.affiliation: Boston University School of Dental Medicine, Department of Molecular and Cell Biology, 72 E. Concord Street Boston MA 02118.
authors.forename: Khalid
authors.initials: K
authors.lastname: Abalkhail
authors.affiliation: Harvard University, Harvard T.H. Chan School of Public Health, 401 Park Drive, Boston MA 02115.
authors.forename: Petros
authors.initials: P
authors.lastname: Koutrakis
authors.affiliation: Boston University School of Medicine, Pulmonary Center, 72 E. Concord Street, Boston MA 02118.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.affiliation: Tufts University School of Medicine, Integrative Physiology and Integrative Biology, 136 Harrison Ave, Boston MA 02111.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Genco
authors.affiliation: Boston University School of Dental Medicine, Department of Molecular and Cell Biology, 72 E. Concord Street Boston MA 02118.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Kukuruzinska
authors.affiliation: Boston University School of Medicine, Department of Medicine, Section of Computational Biomedicine, Boston MA 02118.
authors.forename: Stefano
authors.initials: S
authors.lastname: Monti
authors.affiliation: Boston University School of Dental Medicine, Department of Molecular and Cell Biology, 72 E. Concord Street Boston MA 02118.
authors.forename: Manish V
authors.initials: MV
authors.lastname: Bais
authors.affiliation: Boston University School of Public Health, Department of Environmental Health, 72 E. Concord Street, Boston, MA 02118.
authors.forename: David H
authors.initials: DH
authors.lastname: Sherr
keywords: Aryl Hydrocarbon Receptor; Oral Squamous Cell Carcinoma; environment; microbiota