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Smoothened protein expression and promoter methylation status in serous ovarian carcinomas

Aberrant Hedgehog (Hh) pathway signaling has been implicated in pathogenesis of several human cancers. Recent studies have indicated its active role in serous ovarian carcinomas. Smoothened protein (SMO), a transmembrane co-receptor in Hh pathway signal transduction, is inhibited in non- dividing cells, thus its disinhibition might be a trigger for uncontrolled cell proliferation and growth. Very few studies have explored the role of SMO in serous ovarian cancers. The aim of the study was to assess the expression of SMO protein and to explore the Smoothened gene promoter methylation in a cohort of serous ovarian carcinomas. SMO protein expression was immunohistochemically quantified in 40 high-grade serous carcinomas (HGSC), 12 low-grade serous carcinomas (LGSC), 20 normal ovarian and 9 normal fallopian tube samples (controls). SMO gene promoter methylation status was analyzed using methylation-specific polymerase chain reaction (MSP) in randomly selected HGSCs (n=10), LGSCs (n=10), and normal fallopian tube (n=9) samples. Kaplan-Meier survival plots were used to estimate the impact of SMO expression on patients‘ overall survival (OS). SMO nuclear expression was significantly higher in HGSCs and LGSCs compared with the fallopian tube samples (p=0.010 and p=0.003, respectively). LGSCs, compared with normal ovarian tissue, exhibited higher total, cytoplasmic/membrane and nuclear expression (p=0.000, p=0.001 and p=0.000, respectively). Comparing HGSCs and LGSCs, significantly higher total and cytoplasmic/membrane expression was found in HGSC (p=0.026 and p=0.030, respectively). SMO gene promoter was unmethylated in both LGSCs and HGSCs as well as in fallopian tube. In addition, the SMO protein expression had no significant impact on patients‘ OS (p=0.07). Our data indicate the lack of SMO gene promoter methylation while a significant overexpression (particularly nuclear) of SMO protein characterized a substantial proportion of serous ovarian carcinomas. Further functional studies should elucidate the clinical relevance of these findings.

Hedgehog signaling pathway ; smoothened ; serous ovarian carcinomas

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