EphA2 receptor tyrosine kinase is a tumor suppressor gene in mammalian skin

3962 Overexpression of EphA2 receptor tyrosine kinase is frequently detected in many common types of human cancer and has been correlated with tumor prognosis. This has led to the suggestion that EphA2 is an oncoprotein. This notion predicts that EphA2 gene deletion in vivo will lead to reduced tumor susceptibility. Surprisingly, we report here that EphA2 knockout mice exhibited dramatically increased susceptibility to skin tumorigenesis in the classical DMBA/TPA two-stage carcinogenesis model. Deletion of EphA2 led to several fold increase in tumor multiplicity and significantly shortened tumor latency. Further, tumors in homozygous knockout mice showed significantly accelerated growth and malignant progression toward invasive squamous cell carcinoma. Loss of EphA2 did not appear to affect apoptosis, but was associated with increased tumor cell proliferation. Treatment of primary keratinocytes from wild type mice with ephrin-A1 inhibited ERK1/2 activities and suppressed cell growth; both effects were abolished in EphA2-null keratinocytes. Similar to human cancers, EphA2 expression was elevated in tumor parenchyma compared with adjacent normal tissues, possibly as a result of oncogenic activation of Ras, which is prevalent in DMBA-induced skin tumors and is known to promote transcriptional activation of EphA2 expression. These results demonstrate that EphA2 is a novel tumor suppressor gene in mammalian skin. Overexpression of EphA2 in tumors may represent a compensatory feedback mechanism to negatively regulate tumor growth and progression.