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

机译：核调节剂H19在人肝癌细胞中诱导MDR1相关的耐药性

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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.
机译：获得抗药性是癌症化学疗法中遇到的主要障碍之一。在耐阿霉素的R-HepG2细胞中发现了多药耐药性1（MDR1）基因及其蛋白产物P-糖蛋白的过表达，并伴随着阿霉素蓄积水平的降低，这是通过选择人类肝细胞癌HepG2细胞衍生的亚系与阿霉素。此外，Northern印迹分析显示R-HepG2细胞中印迹的H19 mRNA上调了八倍。通过用反义H19寡核苷酸转染来抑制H19抑制了MDR1 / P-糖蛋白的表达，增加了HepG2亲本细胞和R-HepG2细胞中阿霉素的细胞蓄积水平和致敏的阿霉素毒性。甲基化特异性聚合酶链反应分析的结果表明，MDR1基因启动子在R-HepG2细胞中被低甲基化。反义H19寡核苷酸转染诱导R-HepG2细胞中MDR1启动子甲基化百分比显着增加，MDR1表达降低。因此，据信至少在肝癌细胞中，通过调节MDR1启动子甲基化，H19基因诱导了P-糖蛋白表达和MDR1相关的耐药性。

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