UNRAVELING THE LINKAGE BETWEEN MET AND EGFR FAMILY OF RECEPTORS IN TPL2-RELATED SQUAMOUS CELL CARCINOMA

Cutaneous Squamous Cell Carcinoma (cSCC) is a cancer of the epidermal layer of the skin that affects over 1 million people in the United States each year. The prevalence of cSCC has increased substantially over the past 3 decades, and thus understanding the mechanisms by which it forms is crucial. Development or progression of tumors rely on the absence or presence of tumor suppressor genes and oncogenes. One such tumor suppressor gene is Tpl2, also called MAP3K8 in humans, which is a serine/threonine kinase in the MAPK signaling pathway. This pathway plays a crucial role in the regulation of cell proliferation, differentiation, cell apoptosis and inflammation. Research has shown that when Tpl2 is absent, squamous cell carcinoma is more likely to occur and at a faster rate. The reason for the increase in tumorigenesis in the absence of Tpl2 is still being elucidated. Receptor tyrosine kinase MET and its ligand HGF are upregulated in Tpl2-/- mice. Some recent publications link MET with the EGFR family of receptors. In some models, upregulation or inhibition of either receptor affects the other, suggesting that these two receptors interact to activate downstream signal transduction pathways. To study a possible relationship between MET and the EGFR family of receptors, keratinocytes from Tpl2+/+ and Tpl2-/- mice were treated with inhibitors specific to each receptor alone and in combination. Downstream proteins were analyzed using a variety of methods such as RTK assay, Western blotting, tube formation assay and gelatin zymography. We found that EGFR and MET do interact in our model in terms of activation of downstream signaling, MMP-9 activity and angiogenesis. Further, we identified HER-2 as a protein receptor that may be central to the relationship between EGFR and MET, and therefore should be evaluated further in the future.