期刊
ONCOGENE
卷 26, 期 33, 页码 4877-4881出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.onc.1210266
关键词
H19; MDR1; drug resistance; P-glycoprotein; DNA methylation
Acquisition of drug resistance is one of the main obstacles encountered in cancer chemotherapy. Overexpression of multi-drug resistance 1 (MDR1) gene and its protein product P-glycoprotein, accompanied with a decrease in doxorubicin accumulation level, was observed in doxorubicinresistant R-HepG2 cells, a subline derived by selection of human hepatocellular carcinoma HepG2 cells with doxorubicin. In addition, Northern-blot analysis revealed an eight fold upregulation of the imprinted H19 mRNA in R-HepG2 cells. H19 knockdown bytrans fection with antisense H19 oligonucleotides suppressed the MDR1/P-glycoprotein expression, increased the cellular doxorubicin accumulation level and sensitized doxorubicin toxicityin both HepG2 parent cells and R-HepG2 cells. Results from methylation-specific polymerase chain reaction analysis indicated that the MDR1 gene promoter was hypomethylated in R-HepG2 cells. Antisense H19 oligonucleotides transfection induced a marked increase in the percentage of MDR1 promoter methylation and decrease in MDR1 expression in R- HepG2 cells. Thus, the H19 gene is believed to induce P- glycoprotein expression and MDR1-associated drug resistance at least in liver cancer cells through regulation of MDR1 promoter methylation.
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