Die Rolle der Rap-1/B-Raf-Signaltransduktion in der molekularen Pathogenese von gastroenteropankreatischen neuroendokrinen Tumoren

Molecular pathogenesis of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is largely unknown. Recently, the serine-threonine kinase B-Raf was identified as an oncogene in endocrine cancer such as thyroid carcinoma. In endocrine cells, the small G-protein Rap1 stimulates mitogen-activated protein kinase (MAPK) signaling by activating B-Raf. We examined the expression of Rap1 and B-Raf in GEP-NETs and their contribution to MAPK signaling in neuroendocrine cell lines. In addition, we explored the effect of suppressing B-Raf kinase by the recently developed inhibitor BAY43-9006 (Sorafenib) on growth, apoptosis and MAPK activation neuroendocrine cell lines. METHODS AND RESULTS: Expression of Rap1 and B-Raf in GEP-NETs (19 insulinomas, 15 carcinoid tumors and 10 gastrinomas) was examined by immunohistochemistry, which revealed that Rap1 and B-Raf were highly prevalent in the majority of GEP-NETs. Overexpression of Rap1 and B-Raf activated MAPK extracellular dependent kinase (ERK) ERK-2 and ERK-dependent transcription factor Elk-1 in neuroendocrine cell lines BON and In-R1-G9. Suppression of B-Raf by BAY43-9006 inhibited growth and induced apoptosis in cell lines BON and In-R1-G9. CONCLUSION: These results indicate that Rap1-B-Raf signaling may contribute to pathogenesis of GEP-NETs and provides a molecular target for treatment of GEP-NETs.