[As2O3 induces demethylation and up-regulates transcription of SHP-1 gene in human lymphoma cell line T2 cells]
| Autor: | Lin, Yang, Jian-Min, Luo, Yan, Li, Xiao-Jun, Liu, Shu-Peng, Wen, Xing-Yan, Du, Li, Yao, Jing-Ci, Yang, Zuo-Ren, Dong |
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| Rok vydání: | 2009 |
| Předmět: |
Transcriptional Activation
Dose-Response Relationship Drug Lymphoma Lymphoma Non-Hodgkin Protein Tyrosine Phosphatase Non-Receptor Type 6 Antineoplastic Agents Apoptosis Oxides DNA Methylation Arsenicals Up-Regulation Gene Expression Regulation Neoplastic Proto-Oncogene Proteins c-kit Arsenic Trioxide Cell Line Tumor Humans CpG Islands RNA Messenger Cell Proliferation |
| Zdroj: | Zhonghua zhong liu za zhi [Chinese journal of oncology]. 31(6) |
| ISSN: | 0253-3766 |
| Popis: | To investigate the methylation of CpG island in the SHP-1 gene promoter and its significance in lymphoma. To evaluate the effects of As2O3 on demethylation of SHP-1 in human lymphoma cell line T2 and on proliferation of T2 cells.T2 cells were treated with AsO3. Methylation specific PCR was used to detected the status of SHP-1 methylation in newly diagnosed lymphoma tissues and the T2 cells. The mRNA and protein expression of SHP-1 were determined by FQ-PCR and Western blot. The expression of phospha-c-kit was examined by Westren blot. MTT and flow cytometry were used to determine the growth and apoptosis in T2 cells.T2 cells contained completely methylated SHP-1. Furthermore, there was constitutive c-kit phosphorylation. The expression of SHP-1 was recoverd when the cells exposed to AsO3, and concomitant with increasing SHP-1, a parallel down-regulation of phosphorylated c-kit occurred, so that by day 3 phosphorylated c-kit was barely detectable. As2O3 inhibited the cell growth, and the effects were dose- and time-dependent. As2O3 also increased apoptosis rate of T2 cells in a dose- and time-dependent manner, too, and on the 1, 2, 3 d treatment with AsO3 (2.5 micromol/L), the apoptosis rates were 6.12%, 26.53%, 50.90%, respectively. The frequency of methylation in SHP-1 gene promoter in lymphoma tissues was 87.5% (28/32). In the control group, however, 12 specimens of benign lymph node proliferation showed no methylation in CpG island of SHP-1 gene promoter.Hypermethylation of SHP-1 gene promoter in lymphoma indicates the inactivation of SHP-1 gene and its possible role in the tumorigenesis of lymphoma. As2O3 can effectively cause demethylation and inhibit the growth of tumor by reactivating the SHP-1 gene transcription. SHP-1 methylation leading to epigenetic activation of c-kit may have a tentative role in the pathogenesis of lymphoma. Therefore, As2O3 is potentially useful in the treatment of lymphoma as a demethylating agent. |
| Databáze: | OpenAIRE |
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