| Summary: | <p>Abstract</p> <p>Background</p> <p>The Ras association domain family (RASSF) encodes for distinct tumor suppressors and several members are frequently silenced in human cancer. In our study, we analyzed the role of RASSF2, RASSF3, RASSF4, RASSF5A, RASSF5C and RASSF6 and the effectors MST1, MST2 and WW45 in thyroid carcinogenesis.</p> <p>Results</p> <p>Frequent methylation of the <it>RASSF2 </it>and <it>RASSF5A </it>CpG island promoters in thyroid tumors was observed. <it>RASSF2 </it>was methylated in 88% of thyroid cancer cell lines and in 63% of primary thyroid carcinomas. <it>RASSF2 </it>methylation was significantly increased in primary thyroid carcinoma compared to normal thyroid, goiter and follicular adenoma (0%, 17% and 0%, respectively; p < 0.05). Patients which were older than 60 years were significantly hypermethylated for <it>RASSF2 </it>in their primary thyroid tumors compared to those younger than 40 years (90% vs. 38%; p < 0.05). <it>RASSF2 </it>promoter hypermethylation correlated with its reduced expression and treatment with a DNA methylation inhibitor reactivated <it>RASSF2 </it>transcription. Over-expression of RASSF2 reduced colony formation of thyroid cancer cells. Functionally our data show that RASSF2 interacts with the proapoptotic kinases MST1 and MST2 and induces apoptosis in thyroid cancer cell lines. Deletion of the MST interaction domain of RASSF2 reduced apoptosis significantly (p < 0.05).</p> <p>Conclusion</p> <p>These results suggest that <it>RASSF2 </it>encodes a novel epigenetically inactivated candidate tumor suppressor gene in thyroid carcinogenesis.</p>
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