engleski

The role of the SHH/PTH/SMO pathway in oncogenesis

Signaling pathways that play a fundamental role during development appear to underlie many disease states when misregulated. The mechanism by which activation of the Hedgehog/Patched pathway leads to carcinogenesis is not entirely clear, but the pathway malfunctioning in some tumors has been demonstrated by mutations and/or aberrant expression of its genes. The Hedgehog Patched signaling pathway was first identified in a large Drosophila screen for genes that were required for patterning of the early embryo. In human research the Hedgehog Patched signaling pathway is usually referred to as SHH/PTCH/SMO pathway. Activation of the pathway is initiated through binding of the secreted Hedgehog ligand Hh to its membrane receptor Ptch (12-transmebrane domain protein). This relieves 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 . Other target genes important for the oncogenic function of the pathway are those involved in controlling cell proliferation (cyclin D, cyclin E, Myc, and the components of the epidermal growth factor pathway) and in angiogenesis (components of the platelet-derived growth factor and of the vascular-epithelial growth factor pathway) . 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 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 measure in tumors and in malformations on DNA level as loss of heterozyosity of PTCH and on RNA level by aberrant expressions of particular genes of the pathway. But although we know very little about entire SHH/PTCH/SMO pathway segments, especially about downstream signaling events, or about cellular responses to PTCH inactivation, we may soon be able to interfere with the pathway malfunctioning. Discovery of small molecules which act as agonists of the pathway opens a new avenue for treatment of diseases caused by its aberrant activation.

tumorsupressors; oncogenes; cancer; SHH; PTCH; SMO; signaling pathway

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