MicroRNA-148a is silenced by hypermethylation and interacts with DNA methyltransferase 1 in gastric cancer

被引:126
作者
Zhu, Akao [1 ]
Xia, Jiazeng [1 ]
Zuo, Junbo [1 ]
Jin, Shimao [2 ]
Zhou, Hong [1 ]
Yao, Lubin [1 ]
Huang, Hongyu [3 ]
Han, Zhijun [3 ]
机构
[1] Nanjing Med Univ, Affiliated Wuxi Hosp 2, Dept Gen Surg, Wuxi 214002, Jiangsu, Peoples R China
[2] Nanjing Med Univ, Affiliated Wuxi Hosp 2, Dept Gastroenterol, Wuxi 214002, Jiangsu, Peoples R China
[3] Nanjing Med Univ, Affiliated Wuxi Hosp 2, Cent Lab, Wuxi 214002, Jiangsu, Peoples R China
关键词
MicroRNA-148a; DNA methyltransferase 1; Methylation; Gastric cancer; DE-NOVO METHYLATION; GENE; EXPRESSION; DNMT3A; HYPOMETHYLATION; CARCINOGENESIS; CARCINOMA; TARGETS; CELLS; LONG;
D O I
10.1007/s12032-011-0134-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 [肿瘤学];
摘要
Studies have shown that microRNA-148a (miR-148a) was proved to be silenced while DNA methyltransferase 1 (DNMT1) was over-expressed in gastric cancer. But the mechanism of aberrant expression of miR-148a and DNMT1 and their relationships in gastric cancer are still unknown. The aims of this study were to investigate the expression profile of miR-148a and DNMT1 and reveal whether they have any relationships. We used reverse-transcriptase quantitative real-time PCR, methylation-specific PCR and Western blot to measure the level of miR-148a expression, DNA methylation level and DNMT1 expression, respectively. Gastric cancer cells were transfected with plasmid or siRNA or treated with 5-aza-2'-deoxycytidine. Cell proliferation and apoptosis were detected by cell counting and flow cytometric analysis. In this study, we demonstrated that gastric cancer tissues and cell lines displayed a consistent down-regulation of miR-148a and hypermethylation of promoter region. DNMT1 was over-expressed in primary tumors and cell lines, while knockdown of DNMT1 using siRNA could decrease methylation level of miR-148a promoter and restore its expression. Furthermore, ectopic over-expression of miR-148a in cancer cell lines caused reduction in DNMT1 expression and inhibited cell proliferation, but no obvious change was found in apoptosis rate. These results suggest that miR-148a is inactivated by DNA hypermethylation of promoter region in gastric cancer, which is mediated through DNMT1 over-expression. Additionally, the silence of miR-148a reduces its suppression to DNMT1 in gastric cancer, and this may in turn result in over-expression of DNMT1 and promote DNA hypermethylation.
引用
收藏
页码:2701 / 2709
页数:9
相关论文
共 31 条
[1]
Ardekani Ali M., 2010, Avicenna Journal of Medical Biotechnology, V2, P161
[2]
Acid-sensing ion channels in malignant gliomas [J].
Berdiev, BK ;
Xia, JZ ;
McLean, LA ;
Markert, JM ;
Gillespie, GY ;
Mapstone, TB ;
Naren, AP ;
Jovov, B ;
Bubien, JK ;
Ji, HL ;
Fuller, CM ;
Kirk, KL ;
Benos, DJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (17) :15023-15034
[3]
CLONING AND SEQUENCING OF A CDNA-ENCODING DNA METHYLTRANSFERASE OF MOUSE CELLS - THE CARBOXYL-TERMINAL DOMAIN OF THE MAMMALIAN ENZYMES IS RELATED TO BACTERIAL RESTRICTION METHYLTRANSFERASES [J].
BESTOR, T ;
LAUDANO, A ;
MATTALIANO, R ;
INGRAM, V .
JOURNAL OF MOLECULAR BIOLOGY, 1988, 203 (04) :971-983
[4]
microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer [J].
Braconi, C. ;
Kogure, T. ;
Valeri, N. ;
Huang, N. ;
Nuovo, G. ;
Costinean, S. ;
Negrini, M. ;
Miotto, E. ;
Croce, C. M. ;
Patel, T. .
ONCOGENE, 2011, 30 (47) :4750-4756
[5]
MicroRNA-Dependent Regulation of DNA Methyltransferase-1 and Tumor Suppressor Gene Expression by Interleukin-6 in Human Malignant Cholangiocytes [J].
Braconi, Chiara ;
Huang, Nianyuan ;
Patel, Tushar .
HEPATOLOGY, 2010, 51 (03) :881-890
[6]
The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a [J].
Chédin, F ;
Lieber, MR ;
Hsieh, CL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (26) :16916-16921
[7]
Altered Expression of MiR-148a and MiR-152 in Gastrointestinal Cancers and Its Clinical Significance [J].
Chen, Yue ;
Song, Yongxi ;
Wang, Zhenning ;
Yue, Zhenyu ;
Xu, Huimian ;
Xing, Chengzhong ;
Liu, Zhuangkai .
JOURNAL OF GASTROINTESTINAL SURGERY, 2010, 14 (07) :1170-1179
[8]
RETRACTED: Methylation mediated silencing of microRNA-1 gene and its role in hepatocellular carcinogenesis (Retracted Article) [J].
Datta, Jharna ;
Kutay, Huban ;
Nasser, Mohd W. ;
Nuovo, Gerard J. ;
Wang, Bo ;
Majumder, Sarmila ;
Liu, Chang-Gong ;
Volinia, Stefano ;
Croce, Carlo M. ;
Schmittgen, Thomas D. ;
Ghoshal, Kalpana ;
Jacob, Samson T. .
CANCER RESEARCH, 2008, 68 (13) :5049-5058
[9]
miR-148 targets human DNMT3b protein coding region [J].
Duursma, Anja M. ;
Kedde, Martijn ;
Schrier, Mariette ;
Le Sage, Carlos ;
Agami, Reuven .
RNA, 2008, 14 (05) :872-877
[10]
MicroRNAs and Metastasis: Little RNAs Go a Long Way [J].
Dykxhoorn, Derek M. .
CANCER RESEARCH, 2010, 70 (16) :6401-6406