The Role of the Aryl Hydrocarbon Receptor in Mediating the Migration and Survival of Head and Neck Squamous Cell Carcinoma
Restricted (Penn State Only)
- Author:
- Yusko, Brandon Allen
- Graduate Program:
- Molecular, Cellular, and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- August 18, 2022
- Committee Members:
- Andrew Patterson, Major Field Member
Adam Glick, Major Field Member
Gary Perdew, Chair & Dissertation Advisor
Joshua Lambert, Outside Unit & Field Member
Melissa Rolls, Program Head/Chair - Keywords:
- cancer
toxicology - Abstract:
- The human aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor in the Per-Arnt-Sim (PAS) family of the basic helix-loop-helix (bHLH) superfamily, first identified as a mediator of xenobiotic metabolism. Through the binding of small molecule agonist, predominantly polycyclic aromatic hydrocarbons (PAH) including, 2,3,7,8-tetrachlorodibezo-p-dioxin (TCDD) and benzo[a]pyrene, the AHR translocates to the nucleus. Following heat shock protein 90 displacement with the aryl hydrocarbon receptor nuclear translocator (ARNT), the AHR heterodimer can bind dioxin response elements in the sequence of target genes. Through this signaling process, the AHR not only mediates xenobiotic toxicity, but also participates in a myriad of cellular processes, such as immune surveillance, proliferation, metabolism, and carcinogenesis, through transcriptional regulation. In this way, the role of the AHR as a environmental sensor continues to broaden as advancements in basic research are made. Building on the previous work of the lab, we aimed to further explore the effects of AHR activation and inhibition on the progression of head & neck squamous cell carcinoma (HNSCC) with these studies. This dissertation outlines the work completed to establish the AHR as a mediator of HNSCC migration, invasion, and chemotherapy resistance. First, we aimed to generate a transcriptional profile of AHR modulation in the HNSCC line OSC19 using TCDD treatment as a potent AHR agonist, along with the novel antagonist IK-175. Using RNA-sequencing, we compiled a comprehensive list of differentially expressed genes and sets of enriched biological processes through gene ontology analysis. TCDD treatment enhanced expression of cytokines integral to local invasion of the stroma, inflammatory signaling, and immune cell recruitment and differentiation. Then, we worked to characterize the effects of AHR activation on HNSCC migratory potential in both 2D and 3D culture systems. Using several techniques to assess cell migration and motility, we provide evidence that AHR agonism promotes migratory potential through the upregulation of cytoskeletal reorganizing genes and the suppression of matrix metalloproteinase inhibitors. Finally, our focus turned to the ability of the AHR to influence chemotherapy resistance of HNSCC, with a focus on the chemotherapeutic agent 5-fluorouracil (5-FU). We found that treatment of OSC19 cells with IK-175 sensitized the cells to 5-FU, resulting in greater cell death after treatment and fewer viable colonies in a clonogenicity assay. Taken together, these findings further support the role of AHR as a microenvironmental sensor in the context of HNSCC and suggest AHR antagonism as a potential therapeutic measure to restrict tumor metastasis and increase chemotherapeutic efficacy for patients.