Abstract:

Objective   To analyze the promoter methylation status of multiple tumor suppressor genes (TSGs) (SOCS-1, SOCS-3, 3-OST-2, DLC-1) in endometrial carcinoma (EC) and explore its clinical pathological significances. Methods   Sixty EC samples, 79 hyperplasia endometrium and 27 normal endometrium were collected. We performed methylation specific PCR (MSP) to detect the promoter methylation of the TSGs. The changes of DNA methylation and gene expression before and after the treatment of epigenetic drugs in Ishikawa cells were investigated by MSP and Real-time PCR, respectively. ResultsIn EC, the methylation rate of SOCS-1 and DLC-1 genes was low(13.3% and 21.7%, respectively), and that of SOCS-3 and 3-OST-2 genes was very high (88.3% and 78.3%, respectively). High frequency of SOCS-3 methylation was also found in complex hyperplasia and atypical hyperplasia (53.3% and 54.2%, respectively). 3-OST-2 was positively correlated with tumor differentiation (P＜0.05). Both SOCS-3 and 3-OST-2 complete methylation were detected in untreated Ishikawa cells and were partially reversed by 5-Aza-dC or TSA. Expression of mRNA increased and TSA was more efficient than 5-Aza-dC in inducing the gene expression. After treatment by the combination of the two inhibitors, SOCS-3 and 3-OST-2 methylation was completely reversed and mRNA SOCS-3 and 3-OST-2 significantly increased. Conclusions   SOCS-3 and 3-OST-2 promoter methvlaion is an early and frequent event in EC and the methylation of SOCS-3 occurred earlier than that of 3-OST-2. DNA methylation and histone modifications contribute to the transcriptional regulation of SOCS-3 and 3-OST-2, and there is a cross-talk between them.

Key words: Endometrial neoplasms; Tumor suppressor gene; DNA methylation; Epigenetic