Role of Tristetraprolin in Head and Neck Cancer Progression

Head and neck squamous cell carcinoma (SCC) is one of the ten most common cancers globally, and affects ~500,000 individuals. In the US alone, oral cancer accounts for more deaths annually than cervical cancer, melanoma, or lymphoma and costs ~ 2 billion dollars. The 5-year survival rate is less than 50%, a prognosis that is poorer than breast cancer or melanoma. SCC exhibits high expression of several inflammatory cytokines including IL6, GM-CSF, TNF-á, COX-2 and IL-8. These cytokines contribute to the aggressive phenotype of HNSCC. Proteins such as tristetraprolin (TTP) control cytokine expression by altering mRNA stability. TTP inhibits cytokine expression by promoting degradation of the cytokine mRNA transcript. Therefore, it is likely that downregulation of TTP promotes HNSCC invasion by upregulating cytokine expression. Objective: To investigate TTP expression and its role in SCC progression using cell lines and human tissue. Methods: Immunohistochemistry with TTP and IL6 antibodies was performed on a tissue microarray with pre-treatment biopsies of oropharyngeal SCC. Expression of TTP in SCC cell lines and transient overexpression of TTP were verified by immunoblot analysis. IL6 secretion was quantified by ELISA. Results: Immunoblot analysis of HNSCC cell lines shows variable expression of TTP. Overexpression of TTP in HNSCC cell lines decreased IL6 expression. Tissue microarray findings show that increased IL6 intensity is prognostic for poor disease specific survival and higher probability of tumor recurrence and second primary tumor. The prognostic effect of IL6 on disease specific survival depends on the expression of TTP. Conclusions: Our findings suggest a role for TTP in tumor progression in HNSCC, possibly via IL6 regulation. Further studies will explore the mechanism of this interaction (This study was supported in part by DE018512-01, DE017966, DE018290, P50CA97248, and W81XWH-05-1-0075, DE007057-32).