engleski

Interactions and therapeutic potential of Hh-Gli pathway genes in different tumors

The Hh-Gli signaling pathway also known as Hh-Ptc or Hh/Ptc/Smo plays a major role in embryonic development and its deregulation is related to developmental malformations and tumorigenesis. A distinct role of Hh-Gli pathway in tumors linked to Gorlin syndrome (also known as BCNS or NBCCS) has been defined for ten years, but its involvement is only now becoming apparent in breast, lung, prostate, digestive tract, and other tumors. Normally, a secreted protein Hh (Hedgehog) binds to a transmembrane protein Ptc (Patched), which releases its repression of Smo (Smoothened), also a membrane protein, and triggers a signaling cascade within the cell, finally causing expression of target genes. One of those genes is a transcriptional factor Gli1, involved in cell proliferation, the other is PTCH itself, which limits, and finally blocks the pathway. Recent findings contribute to existence of two hypothetical models of abnormal Hh-Gli pathway activation. One model (on BCCs and ovarian fibromas), suggests constitutive activation of the pathway within the cell, and does not require outside stimulation. The other model, on lung and breast tumors suggests abnormal Hh stimulation from the surrounding cells, which causes a strong intracellular response of the pathway. We analyzed therapeutic potential in blocking and reactivation of the pathway on dermoids, tumors that develop from embryonic stem cells ; they show elements of both developmental malformations and tumors. Also, in dermoid cysts we showed the epigenetic inactivation of PTCH gene (our results so far suggest promoter methylation), and also the role of its haploinsufficiency. Different cell lines derived from each primary culture of ovarian dermoids showing heterogeneous nature, and therefore present a good model for expression analyses of Hh-Gli signaling pathway related genes (Shh, Ptch, Smo, Gli 1, 2, 3). In some cases the high levels of expression of tested genes were efficiently blocked with cyclopamine, and then the pathway was reactivated with Shh. Additionally, clones that have not responded to cyclopamine, or to reactivation of the pathway support another hypothetical model. Our results contribute to insights into mechanisms and roles of disrupted activation of Hh-Gli signaling and its interactions with other cellular processes that affect its activity.

Hh-Gli pathway ; tumors ; therapeutic potential

nije evidentirano