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. 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.

Quinolinate as a Marker for Kynurenine Metabolite Formation and the Unresolved Question of NAD+ Synthesis During Inflammation and Infection

“…AHR activation in lung fibroblasts significantly enhanced migration via generation of arachidonic acid metabolites (88). AHR agonists also significantly increased migration of squamous cell carcinoma cells in culture (89). Our data are consistent with these findings and suggest that kynurenine metabolites lead to changes in the expression levels of HSP90-related proteins that impact on cell motility and other cellular behaviors.…”

Role of the aryl hydrocarbon receptor in carcinogenesis and potential as an anti-cancer drug target

“…This “protective” effect may be significant; however, AhR overexpression was also associated with increased anchorage-independent growth and cell proliferation and this is consistent with other studies in lung cancer cells. The AhR is also pro-oncogenic in head and neck and oral cancers and AhR agonists enhance cell growth and survival, whereas AhR antagonists exhibit anticancer activity, demonstrating a possible role for these compounds in clinical applications (DiNatale et al 2011; DiNatale et al 2012; Stanford et al 2016a). The AhR is expressed in esophageal cancer and leukemia/lymphomas; however, the function of the AhR and its ligands are not well defined, although one study showed that β-naphthoflavone significantly inhibited invasion of esophageal cancer cells.…”

Role of AhR in regulating cancer stem cell–like characteristics in choriocarcinoma

“…These floating spheres also overexpressed stem cell-related genes (Oct-4, Nanog, and Sox-2) and stem cell markers (CD133 and CD44) and had strong proliferative and invasive abilities. Increasing evidence suggested that the activation of AhR dramatically increased the development of CSCs [25][26][27]. All these results suggested that AhR facilitated tumorigenesis in part through the maintenance of cells with CSC characteristics.…”