Date of Award

2014

Embargo Period

8-1-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Oral Health Sciences

College

College of Graduate Studies

First Advisor

Keith Kirkwood

Second Advisor

Terry Day

Third Advisor

Zihai Li

Fourth Advisor

Dennis Watson

Fifth Advisor

M. Rita Young

Abstract

Head and neck cancer accounts for approximately 6% of diagnosed malignancies in the United States, with an estimated 35,000 incidences and over 7,000 deaths every year. Head and neck squamous cell carcinoma (HNSCC) comprises the majority of head and neck cancers, with a worldwide incidence of more than 500,000 cases. Head and neck cancer patients often present in advanced stages of disease, and despite ongoing research, survival rates remain lower than other more common malignancies. Cytokines and pro-inflammatory factors have been shown to have a critical role in the various steps of malignant transformation, including tumor growth, survival, invasion, angiogenesis, and metastasis. Mitogen-activated protein kinases (MAPK), such as p38, JNK, and ERK, relay information from extracellular signals to the effectors that control these diverse cellular processes. Negative regulation of MAPK activity is provided by MAPK phosphatases that dephosphorylate MAPK proteins. The founding member of this class of phosphatases is dual-specificity phosphatase-1 (DUSP1) and has been shown to be crucial for negatively regulating innate immune responses. Initial studies revealed significant over-expression of DUSP1 in a range of human epithelial tumors including prostate, colon, and bladder, with loss of DUSP1 expression in tumors of higher histological grade and in metastases. Based on the above, this study hypothesized that DUSP1 is a negative regulator of tumor-promoting inflammation in head and neck cancer. To test this hypothesis, we first assessed the effect of Dusp1 deficiency in animal models of tumor progression. Dusp1 deficiency enhanced tumor progression in a carcinogen-induced model of oral cancer with higher levels of inflammatory infiltrate and gene expression. Deficiency in hematopoietic-derived cells by bone marrow transplant did not recapitulate the advanced disease phenotype seen in Dusp1 deficient animals. However, Dusp1 deficiency also enhanced the progression of subcutaneous syngeneic breast and prostate allograft tumors. Examination of Dusp1 deficient bone marrow macrophages revealed enhanced expression of inflammatory cytokine IL-1β after stimulation with lipopolysaccharide. Elevated levels of IL-1β were shown to be due to increased de novo transcription in addition to enhanced mRNA stability. Inflammasome activation was not affected by Dusp1 deficiency. Lastly, in human HNSCC tissues, both mRNA and protein DUSP1 was decreased in tumor compared to adjacent non-tumor samples, and IL-1β protein was increased. These studies demonstrate DUSP1 expression is deregulated in HNSCC and suggests an important role for DUSP1 as a negative regulator of tumor-promoting inflammation through suppression of inflammatory cytokines, such as IL-1β. Understanding the role of these inflammatory mediators and the upstream signaling pathways in the tumor microenvironment in head and neck cancer may yield novel therapeutic targets for prevention and treatment.

Rights

All rights reserved. Copyright is held by the author.

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