engleski

Role of the Hedgehog/Patched Signaling Pathway in Oncogenesis. Alterations of PTCH are Attributed to the Pathway Activation in Ovarian Fibromas and Dermoids

Signaling pathways that play a fundamental role during development appear to underlie many disease states when misregulated. The Hedgehog /Patched signaling pathway was first identified in a large Drosophila screen for genes that were required for patterning of the early embryo. Activation of the pathway is initiated through binding of the secreted Hedgehog ligand Hh to its membrane receptor Ptch (12-transmebrane domain protein) relieving the co-receptor Smo (another membrane protein), which was repressed by Ptch, and activates a cascade that leads to translocation of the active form of the transcription factor Gli to the nucleus. PTCH acts as a negative regulator of Hedgehog signaling. When the second large extracellular loop, essential for ligand binding, is deleted by a PTCH mutation, Hh binding to Ptch cannot occur, but repression of Smo is unaffected. When a C-terminal truncation is caused by a PTCH mutation, Ptch can no longer repress Smo, but Hh binding to Ptch is unaffected. Basal cell carcinoma (BCC) of the skin is the most common type of cancer in humans, and many of the genes found mutated in BCCs are members of the SHH/PTCH/SMO pathway. Although most BCCs are sporadic (i.e. they are found in otherwise healthy subjects), their incidence is particularly high (about 90%) in rare individuals with Gorlin syndrome. This heritable disease, associated with mutations in PTCH, predisposes to multiple skin and other tumors and to a variety of malformations. Mutations in PTCH have been identified in some other tumors types, except BCC, like medulloblastoma and meningioma, neuroectodermal tumors, breast carcinomas, squamous cell carcinoma and trichoepithelioma. Most mutations have resulted in protein truncation. Aberrations of the Hedgehog/Patched signaling we studied in tumors and in malformations on DNA level through loss of heterozyosity of tumor suppressor PTCH, and on RNA level by aberrant expressions of particular genes of the pathway, in some cases cDNA microarray analyses were performed or immunochemical detections of the proteins. The aim of our study was to detect involvement of PTCH and of the entire signaling pathway in pathogenesis of ovarian fibroma tumors, BCCs, and dermoids. Dermoids were used in this study as representative of malformations in which mutations of PTCH and aberrations of the Hedgehog /Patched signaling might occur. Alterations of PTCH indicated in one third of ovarian fibromas and dermoids exhibit LOH in the vicinity of the PTCH1 locus, barely affecting its expression. PTCH is also a target gene ; its increased synthesis found in some samples can be attributed to the pathway activation. However, it is interesting that GLI overexpression does not coincide with that of PTCH, and is found only in small proportion of cases. Summarily our results showed high levels of SHH almost regularly, especially in dermoids, usually accompanied by increased expression of SMO. This might indicate that the tissue is constantly exposed to Shh signaling. Although our observations do not really clarify mechanisms of pathway functioning, recent results may contribute to it.

tumor suppressor; PTCH; signaling pathway

nije evidentirano