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

W P Tsang1, T T Kwok

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

Oncogene
|February 14, 2007
PubMed

Insights

The imprinted H19 gene promotes multi-drug resistance 1 (MDR1) expression and doxorubicin resistance in liver cancer cells. H19 knockdown reverses this by increasing MDR1 promoter methylation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Drug resistance is a major challenge in cancer chemotherapy.
  • Hepatocellular carcinoma (HCC) cells can develop resistance to drugs like doxorubicin.
  • The multi-drug resistance 1 (MDR1) gene and its protein P-glycoprotein are key factors in this resistance.

Purpose of the Study:

  • To investigate the role of the imprinted H19 gene in doxorubicin resistance in HCC cells.
  • To explore the relationship between H19, MDR1 expression, and epigenetic modifications.

Main Methods:

  • Developing doxorubicin-resistant HepG2 cells (R-HepG2).
  • Analyzing H19 mRNA levels using Northern blot.
  • Modulating H19 expression with antisense oligonucleotides.
  • Assessing MDR1/P-glycoprotein expression and doxorubicin accumulation.
  • Examining MDR1 promoter methylation using methylation-specific PCR.

Main Results:

  • R-HepG2 cells showed increased MDR1/P-glycoprotein and decreased doxorubicin accumulation.
  • H19 mRNA was significantly upregulated in R-HepG2 cells.
  • H19 knockdown reduced MDR1/P-glycoprotein, increased doxorubicin accumulation, and sensitized cells to doxorubicin.
  • MDR1 promoter was hypomethylated in R-HepG2 cells; H19 knockdown increased methylation and decreased MDR1 expression.

Conclusions:

  • H19 gene upregulation contributes to MDR1-mediated doxorubicin resistance in liver cancer.
  • H19 influences MDR1 expression, at least partly, by regulating MDR1 promoter methylation.
  • Targeting H19 may be a potential strategy to overcome drug resistance in HCC.

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