Hedgehog signaling pathway and basal cell carcinomas (BCC)

Basal cell carcinoma (BCC) of the skin is the most common human cancer, and shows a conitnously increasing incidence. BCCs occur predominantly on sun-exposed skin of elderly fair-skinned people. Several tumor suppresor genes and oncogenes have been implicated in the pathogenesis of BCCs, and most of them are members of the Hedgehog signaling pathway. Hedgehog signaling pathway is one of the most fundamental signal transduction pathways in embryonic development and is required in vertebrates for the normal development of many structures, including the neural tube, axial skeleton, skin and hair. Patched is a part of the Hedgehog-Gli signaling pathway. Patched is a 12-pass transmembrane protein which acts as a receptor for Hedgehog. When Hedgehog protein is not present, Patched represses the activity of Smoothened, another transmembrane protein. In case of Hedhegog binding to Patched, the repression is alleviated, and Smoothened is able to transmit the signal downwards toward transcription factors. When the signal is absent transcription factor Gli is located in the cytoplasm, where it is inactive. If Smoothened is activated, Gli transcription factor is ubiquitinated and transferred into nucleus. There it is responsible for target gene transcription, including Patched itself. Aberrant activation of the pathway in adult tissue is associated with the development of basal cell carcinoma (BCC), medulloblastoma, and also pancreatic, gastrointestinal and other cancers. We are investigating the role of pathway genes in sporadic BCCs underlining their importance in pathogenesis of the disease.