engleski

Genetic and epigenetic regulation of Hh-Gli signaling pathway in ovarian tumors

Hedgehog-Gli is a signaling pathway involved in embryonic development and its malfunctioning is often associated with tumorigenesis. Binding of the ligand protein Hedgehog to its receptor Patched (Ptch) causes Ptch to relieve its repression of the co-receptor Smoothened (Smo). Smo then activates a signaling cascade which activates transcription factor Gli which translocates to the nucleus and induces transcription of target genes. These are genes involved in cell cycle progression and proliferation, and also Ptch itself, which acts as a negative regulator of the pathway. Mutations in Ptch, a tumor suppressor gene, are the cause of a genetic disorder named Gorlin syndrome. Gorlin syndrome is characterized with multiple malformations (pits of palm and soles, spina bifida, cleft lip and palate, hydrocephalus) and tumors (basocellular carcinomas, dermoids of heart and ovary, medulloblastoma). Malfunctioning of this pathway is also involved in various sporadic tumors not associated with the syndrome, namely lung, colon, skin, ovarian and breast). We investigated function of this pathway in sporadic cases of ovarian dermoids and fibromas. We examined expression of various pathway genes and found it was deregulated, but mutation analysis showed no mutations and little LOH events. That led us to examination of methylation status of PTCH promoter. We found increased methylation in both ovarian dermoids and fibromas in relation to normal ovarian tissue. We concluded that aberrant methylation is one of the steps in tumorigenesis of these types of tumors.

genetics ; epigenetics ; Hh-Gli signaling pathway ; PTCH promoter

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