Regulation of EMT markers by the KISS1 metastasis suppressor gene

5375 Epithelial to mesenchymal Transition (EMT) is a normal developmental process in which epithelial cells temporarily acquire mesenchymal characteristics. EMT is also proposed to be a mechanism used by neoplastic cells to escape the primary tumor and migrate into the circulatory system, which are key steps in metastasis. Three genes central to EMT - SNAI1 (SNAIL), SNAI2 (SLUG) and TWIST (TWIST) - repress E-cadherin, which thought to be the critical regulatory change for EMT. We hypothesized that the KISS1 metastasis suppressor might regulate EMT. Re-expression of KISS1 in metastatic human C8161.9 melanoma cells blocks metastasis without inhibiting orthotopic tumor growth. At both the protein and RNA levels, KISS1 re-expression reduced SNAIL, but not TWIST, compared to vector control. E-cadherin RNA expression is restored in the C8161.9KISS1. Genes regulated by SNAIL, such as VEGF and IL-8, are also reduced in C8161.9KISS1. Since KISS1 is secreted, we investigated whether deletion of the secretion signal (KFMΔSS) had an effect on these EMT markers. Neither SNAIL nor TWIST expression was affected by KFMΔSS yet E-cadherin was re-expressed at the RNA level. These studies suggest that KISS1 may suppress metastasis, in part, by modulating processes involved in EMT. The data further suggests alternate roles of KISS1 or KISS-derived peptides inside the cell.
 Support: Natl. Fndn. for Cancer Res, CA87728, F32CA113037, and Komen PDF 1122006