Orphan nuclear receptor LRH-1 promotes oxaliplatin resistance in hepatocellular carcinoma cells by regulating MDR1 gene
- Author:
LIU Jinlian
;
PAN Nan
;
CHEN Xue
;
XIAO Lijia
- Publication Type:Journal Article
- Keywords:
The liver receptor homolog-1;
oxaliplatin;
hepatocellular carcinoma;
multidrug resistance gene 1
- From:
China Tropical Medicine
2024;24(5):506-
- CountryChina
- Language:Chinese
-
Abstract:
Abstract: 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 dosedependent 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.
- Full text:20250617165448628822.Orphan nuclear receptor LRH-1 promotes oxaliplatin resistance in hepatocellular carcinoma cells.pdf
