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DNA promoter methylation status and protein expression of SHh and IHh in serous ovarian carcinomas

Background: The Hedgehog (Hh) signaling pathway is an evolutionarily conserved pathway of signal transmission which plays a significant role in the normal embryonic development of invertebrates and vertebrates. In the adult organism, Hh signaling pathway is mostly inactive or poorly active while its hyperactivation is associated with carcinogenesis. Binding of the Hh ligands, Sonic Hedgehog (SHh), Indian Hedgehog (IHh) and Desert Hedgehog (DHh) along with PTCH protein activates Hh signaling resulting in increased activity of the GLI transcription factors that activate targeted genes. The status of Hh pathway components in serous ovarian carcinomas is poorly understood. Methods: Formalin-fixed paraffin- embedded samples of 11 low-grade (LGSC), 40 high- grade serous ovarian carcinomas (HGSC) and 7 normal/benign ovarian tissues (controls) were used for this study. SHh and IHh protein expression was explored using immunohistochemistry. DNA methylation pattern of SHh and IHh gene was analyzed by methylation-specific PCR (MSP). Results: SHh and IHh expression was significantly higher in both LGSC (p<0.001 and p=0.011, respectively) and HGSC (p<0.001 and p=0.003, respectively) compared with normal/benign ovarian tissues. There was no statistically significant difference in SHh and IHh protein expression between LGSC and HGSC. SHh and IHh DNA methylation was observed in HGSC [(2/40, 5%) and (1/40, 2.5%), respectively]. In all normal ovarian tissues no methylation was detected. Conclusions: A significant proportion of serous ovarian carcinomas exhibits increased SHh and IHh protein expression, which indicates that these Hedgehog signaling pathway components may be actively involved in pathogenesis of serous ovarian carcinomas. Therefore, SHh and IHh might serve as potential therapeutic targets for serous ovarian carcinomas. Low methylation levels of the respective genes in HGSC and absence of methylation in LGSC and normal ovarian tissues indicate alternative mechanisms of SHh and IHh activation. Further clinical studies should confirm the clinical and therapeutic relevance of the observed Hh alterations.

serous ovarian carcinoma ; Hedgehog signaling pathway ; SHh ; IHh

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