p38 MAPK/DUSP1 Axis in Stromal-mediated Tumorigenesis.

Keith Kirkwood, Medical University of South Carolina

Head and neck squamous cell carcinoma (HNSCC) comprises the major 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. We hypothesized that DUSP1 is a negative regulator of tumor-promoting inflammation in head and neck cancer. Dusp1 deficiency enhanced tumor progression in a carcinogen-induced model of oral cancer with higher levels of inflammatory infiltrate and gene expression. 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-1beta after stimulation with lipopolysaccharide. Elevated levels of Il-1beta 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-1beta 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-1beta.