engleski

Melanomas and basal cell carcinomas of the skin use Hh-gli signaling for cell cycle regulation

Hh-Gli pathway has received increasing attention as a crucial regulator of not only embryonic organogenesis but as an oncogenic pathway implicated in diverse human tumors. The pathway begins with binding of the ligand protein Hedhegog to the transmembrane receptor Patched (Ptch), which then releases its inhibition of Smoothened and a cytoplasmatic cascade of phosphorylation and dephosphorylation events leads to activation of transcription factor Gli and transcription of target genes, which include Cyclin D, Cyclin E, members of Wnt and TGFbeta signaling pathways, and Ptch itself. We intend to find connections between two different aspects of cell function, through the role of PTCH in Hh-Gli pathway and p16 in cell cycle, in cutaneous melanoma and basal cell carcinoma as two most frequent skin neoplasias. The CDKN2A locus encoding a cyclin-dependent kinase inhibitor p16 acts to inhibit cell cycle progression in the G1 phase by binding and inhibiting CDK4/6 kinases. Loss of p16 leads to deregulated CDK4/6 action and promotion of cell divisions. Our recent results indicate general integration of Hh-Gli signaling pathway and cell cycle, that contributes to discoveries by others on integration of Hh-Gli and other proliferating pathways Ras/Akt, and PI3K. In basal cell carcinoma of the skin (BCC), we often found LOH of the PTCH1 locus. Alterations of PTCH expression in those tissues did not always follow GLI overexpression but we almost regularly detected high levels of SHH, accompanied by increased expression of SMO. In melanoma we have found LOH in p16 region, indicating mutations in p16 affecting cell cycle regulation. Ptch activity on normal skin is not immunohistochemically detectable, its highest activity we have seen in BCCs, but also very often we detected high activity of p16. Those results we explained through its known role in cell cycle, by Ptch-cyclin B interaction and progression of G1 phase of cell cycle, and by our findings of Ptch-cyclin D interaction and progression of G2 of cell cycle. In melanoma beside higher p16 activity, we also found higher Ptch activity, that would contribute to recent findings of requirement of Hh-Gli signaling in melanoma pathogenesis. In melanoma pathology the Hh-Gli pathway has been implicated very recently and seems to be promising in therapeutic strategies. Although involvement of p16 in melanoma development has been shown either through loss of heterozygosity or mutation screenings of p16, connections to the HH-Gli pathway have not been shown until recently.

melanomas; BCCs; Hh-Gli signaling

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