engleski

Different tumors require Hh-Gli signaling through 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. 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 basocellular carcinomas of the skin, ovarian fibroma and ovarian dermoids, we often found LOH of the PTCH1 locus. Alterations of PTCH expression in those tissues did not always follow GLI overexpression but high levels of SHH are almost regularly detected, especially in dermoids accompanied by increased expression of SMO (Levanat et al, Ann NY Acad Sci, 2004). Our recent results of methylation status on different tumors (basocellular carcinoma of the skin, dermoid cysts, ovarian fibromas) explains difference in expression of GLI1 and PTCH according to methylated CpG regions in a PTCH promoter. Two promoter regions showed statistically significant hypermethylation in ovarian tumors compared to healthy controls ; more significantly in the vicintiy of Gli-binding sites and less significantly in the region containing ATG codon. But, in basocelluar carcinomas of the skin we observed no difference in methylation, suggesting different mechanisms of neoplasia and activation of Hh-Gli pathway (Cretnik et al, Int J Mol Med, 2007). We intend to investigate and to find connections between two different aspects of cell function, through the role of PTCH and p16 in pathogenesis of cutaneous melanoma and basal cell carcinoma as two most frequent skin neoplasias with different pathology. Basocellular carcinoma involves PTCH1 loss-of-function, including gain-of-function in SHH, SMO and GLI proteins, dominantely based on mutations in tumor supresor Ptch. In melanoma pathology, indications of connections to the Hh-Gli pathway started to be promising in therapeutic strategies very recently. 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 are very new interaction. 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. 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. We tried to explain those results through its known role in cell cycle, where role of Ptch can be manifested by cyclin B interaction and therefore progression of G1 phase of cell cycle (Barnes et al, EMBO J, 2001) and, then by cyclin D (Levanat et al, Int J Mol Med, 2004) and G2 of cell cycle. In melanoma we also found higher Ptch activity, that would contribute to recent findings of requirement of Hh-Gli signaling in melanoma pathogenesis. Those results, along with successful tumor growth inhibition in cell cultures by cyclopamine, will contribute to better understanding of the mechanisms of Hh-Gli pathway

Hedgehog signaling; cancer

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