engleski

Hedgehog signaling pathway status in serous ovarian carcinomas

Background: Hedgehog (Hh) signaling pathway is a highly conserved signaling pathway involved in cell proliferation and differentiation as well in cell polarity in early embryogenesis and morphogenesis. In adults, it is usually inactive while its hyperactivation is associated with carcinogenesis. Hh signaling pathway is activated via binding of the Hh ligands with PTCH transmembrane protein resulting in increased activity of the GLI transcription factors that subsequently activate targeted genes. PTCH1 acts as a tumor suppressor while GLI1 and GLI3 factors have the opposite transcription activities (former has activating and later mainly inhibiting activity). Design: Formalin-fixed paraffin- embedded samples of 52 ovarian serous carcinomas (low-grade [LGSC, n=11] and high-grade [HGSC, n=41]) were explored for PTCH1, GLI1 and GLI3 expression using immunohistochemistry. PTCH1 DNA methylation status was assessed using methylation- specific PCR assay (MSP). Five normal/benign ovarian tissues served as controls. Results: PTCH1 nuclear expression was significantly higher in both LGSC and HGSC compared with normal/benign ovarian tissue (p<0.001 and p<0.001, respectively) while cytoplasmic PTCH1 protein expression was significantly higher in normal ovaries compared with both LGSC and HGSC (p=0.003 and p<0.001, respectively). PTCH1 DNA methylation was exclusively observed in HGSC (6/41, 15%). GLI1 protein expression was significantly higher in HGSC compared with normal ovaries (p=0.032) while GLI3 protein exhibited significantly higher expression in both LGSC and HGSC in comparison with normal ovaries (p<0.001 and p<0.001, respectively). Notably, GLI3 protein had a higher expression in LGSC compared with HGSC (p=0.043). Conclusion: Hedgehog signaling pathway components PTCH1, GLI1 and GLI3 appear to be actively involved in pathogenesis of serous ovarian carcinomas. A significant proportion of serous ovarian carcinomas exhibits aberrant (nuclear) PTCH1 protein expression. Therefore, PTCH1 may play an active transcriptional role in LGSC and HGSC. A subset of HGSC may have PTCH1 gene deregulation caused by its promoter methylation. Further studies involving more samples should confirm these findings and their clinical relevance.

ovarian carcinoma ; serous ovarian carcinoma ; Hedgehog signaling pathway ; PTCH1 ; GLI1 ; GLI3

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