| Summary: | 碩士 === 國防醫學院 === 微生物及免疫學研究所 === 98 === 英文摘要(Abstract)
Hepatocellular carcinoma (HCC) and cervical cancer are major malignancy worldwide. HCC is the second most common fatal cancer in Asia and Africa; and cervical cancer is the fifth most deadly cancer in women worldwide. In addition to genetic deletions and mutations, many studies suggested that epigenetic alterations including DNA methylation and histone modification are also involved in inactivation of tumor suppressor genes (TSG). In our previous data, we have proved that NKX6.1 promoter is hypermethylated in cervical cancer and liver cancer. Moreover, we have showed that NKX6.1 can inhibit tumor cell transformation and invasion. Hence, we would like to further elucidate what mechanism is involved in the epigenetic silencing of NKX6.1 in human cancers.
At first, we cloned and determined the putative promoter of NKX6.1 by luciferase reporter assay. The promoter region (P2) containing about 1.6 kb showed the promoter activity. Secondly, we found the promoter activity of NKX6.1 can be influenced by in vitro methylating. At the same time, we found the Sp1 site in the NKX6.1 promoter region is important for P2 promoter activity. Furthermore, we use RNA interference (RNAi) to knock down human DNA methyltransferases (DNMTs); however, the NKX6.1 expression level was no significantly restored. When we treated cells with Trichostatin A (TSA), a histone deacetylase inhibitor (HDACi), the P2 promoter activity increased. Thesse data suggested that promoter methylation and histone modification may take part in epigenetic silencing of NKX6.1 in human cancers. In future, we want to further elucidate whether HDAC and SP1 are involved in the epigenetic silencing of NKX6.1.
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