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Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells

Oncogene volume 26, pages 4877–4881 (2007)Cite this article

Abstract

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 doxorubicin-resistant 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 by transfection with antisense H19 oligonucleotides suppressed the MDR1/P-glycoprotein expression, increased the cellular doxorubicin accumulation level and sensitized doxorubicin toxicity in 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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Acknowledgements

We are grateful to Professor KP Fung (Department of Biochemistry, The Chinese University of Hong Kong) for providing the R-HepG2 subline. This work was supported by an Earmarked Grant (CUHK4270/04M) from Hong Kong Research Grants Council.

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  1. Department of Biochemistry, The Chinese University of Hong Kong, Hong Kong SAR, China

    W P Tsang & T T Kwok

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  1. W P Tsang
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Correspondence to T T Kwok.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Tsang, W., Kwok, T. Riboregulator H19 induction of MDR1-associated drug resistance in human hepatocellular carcinoma cells. Oncogene 26, 4877–4881 (2007). https://doi.org/10.1038/sj.onc.1210266

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