engleski

Hedgehog-Gli signaling pathway interactions and therapeutic potential in proliferative tumors of the ovary

The Hh-Gli signaling pathway known as Hh-Ptc or Hh/Ptc/Smo plays a major role in embryonic development and deregulated cause developmental malformations and tumorigenesis. The pathway involvement in breast, lung, prostate, digestive tract and other tumors becoming apparent recently. Normally secreted protein Hh (Hedgehog) binds to a transmembrane protein Ptc (Patched), releasing repression of Smo (Smoothened), a membrane protein, triggering a signaling cascade within the cell, finally causing expression of target genes, a tracriptional factor Gli, onvolved in cell proliferation , PTCH itself, which limits, and finally blocks the pathway, than cyclin D, cyclin E, members of WNT and TGF beta signaling pathways. Recent findings suggest two hypothetical models of abnormal Hh-Gli pathway activation. One model (on basocellular carcinomas of ther skin (BCCs) and ovarian fibroma), suggests constitutive activation of the pathway within the cell, and doesnot require outside stimulation. The other on lung and breast tumors suggest abnormal Hh stimulation from the surrounding cells, whichcauses a strong intracellular response of the pathway. Our studies of the pathway activation on human tumors:dermoids (develop from embryonic stem cells ; they show elements of both developmental malformations and tumors) and ovarian carcinomas. Serum-starved or normally grown primary cells were treated with either cyclopamine, tomatidine or Shh protein. Some of the clone lines were additionally analyzed by immunofluorescent staining and flow cytometry (propidium-iodine staining).Immunofluorescet staining of inducible cells showed changes in protein localization before and after induction, confirming that Hh-Gli pathway is fully functional in these cells. In dermoids we showed epigenetic inactivation of PTCH gene (promoter methylation), and also the role of its haploinsufficiency, while in ovarian carcinomas inactivation of the PTCH gene is mostly a consequence of deletions in first ten exons. Also, interactions with other pathways as WNT pathway are related to some extend on borderline tumors.

signaling pathwy ; interactions ; tumors

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