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Expression and localization of Hedgehog-Gli signalling pathway proteins in ovarian dermoids

Hedgehog-Gli signaling pathway is involved in embryonic development, and its malfunctioning is often associated with tumorigenesis and developmental malformations. The entire pathway is still not completely elucidated. It begins with binding of the ligand protein Sonic Hedhegog (Shh) to the transmembrane receptor Patched (Ptch). Ptch then releases its inhibition of Smoothened (Smo), and a cytoplasmatic cascade of phosphorylation and dephorsphorylation events leads to activation of transcription factor Gli and transcription of target genes, which include Cyclin D, Cyclin E, members of Wnt and TGF signaling pathways, and Ptc itself. Interest in Hedgehog-Gli pathway increased recently because of its evident involvement in fatal tumors, like lung, pancreatic and prostate cancers. Hereditary mutations in Ptch gene are the cause of Gorlin syndrome, characterized by various developmental malformations (cleft lip and palate, pits on palms and soles, bifid spine, holoprosencephaly… ) and tumors (basocellular carcinomas, dermoid cysts, fibromas of the ovary and heart, medulloblastoma… ). We present an investigation of Hh-Gli signaling pathway in sporadic cases of ovarian dermoids not associated with Gorlin syndrome. In this work we focus on primary cell cultures derived from human tumors. We developed primary cell cultures from ovarian dermoid tissue and several different clone lines were developed from the same tumor sample. Real-Time PCR demonstrated expression of the Hh-Gli pathway genes. This expression, although present in all clone lines, differs among them, confirming the heterogeneity of this tumor type. Immunofluorescent staining shows difference in localization of some of Hh-Gli pathway proteins among the clone lines, and some of them show reactivity to treatment with the pathway antagonist (cyclopamine) or ligand (Shh protein), on both mRNA and protein level. Taken together, this data suggests Hh-Gli pathway involvement in tumorigenesis and cell cycle progression of ovarian dermoids.

Hh-Gli signaling; primary cultures; ovarian dermoid

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