Orphan nuclear receptor LRH-1 promotes oxaliplatin resistance in hepatocellular carcinoma cells by regulating MDR1 gene
Objective To investigate the function and molecular mechanism of LRH-1 in regulating the sensitivity of hepatocellular carcinoma(HCC)cells to oxaliplatin,providing new ideas for the treatment of liver cancer.Methods Knockdown and overexpression of LRH-1 in HCC cell lines were constructed,and the effect of LRH-1 on oxaliplatin resistance of HCC cells was explored by detecting IC50,cell proliferation,and plate colony formation assay.The transcriptional regulation of the MDR-1 gene by LRH-1 was detected through quantitative PCR.The transcriptional activation ability of LRH-1 on the MDR1 gene was evaluated by luciferase reporter assay.Results In HuH7 cells overexpressing LRH-1,the IC50 significantly increased to 18.012 μmol/L under oxaliplatin treatment,significantly higher than the 2.042 μmol/L in the HuH-7 control group,showing statistically significant differences(P＜0.05).After overexpression of LRH-1 in HuH-7 cells,the cell proliferation ability was significantly increased,with a noticeable increase in MDR1 mRNA level.In HepG2 cells with knockdown LRH-1 expression,the IC50 significantly dropped to 1.012 μmol/L,significantly lower than the 6.294 μmol/L in the HepG2 control group,with statistically significant differences(P＜0.05).After knockdown of LRH-1 in HepG2 cells,the cell proliferation and plate colony formation ability were significantly inhibited,with a notable decrease in MDR1 mRNA expression level.Luciferase reporter assay confirmed that LRH-1 can activate the transcriptional activity of the MDR1 promoter in a dose-dependent manner,and its specific inhibitor ML-180 can significantly reduce LRH-1's transcription activation ability on the MDR1 promoter.Conclusions LRH-1 may promote oxaliplatin resistance in hepatocellular carcinoma cells by regulating the transcriptional activity of MDR1 gene.Since its specific small molecule inhibitor has been successfully synthesized,LRH-1 can potentially become a target for the treatment of drug resistance in hepatocellular carcinoma.
The liver receptor homolog-1oxaliplatinhepatocellular carcinomamultidrug resistance gene 1
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