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Pooled shRNA Library Screening to Identify Factors that Modulate a Drug Resistance Phenotype
Published on: June 17, 2022
The miR-491-3p/Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma
Yang Zhao1, Xinming Qi1, Jing Chen1
1Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China; Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, University of Chinese Academy of Sciences, Beijing 100049, China.
Abstract:
As one of main obstacles in the treatment and prognosis of hepatocellular carcinoma (HCC), multidrug resistance (MDR) is usually associated with the overexpression of the drug efflux pump P-glycoprotein (P-gp/ABCB1) which is responsible for reducing the intracellular concentration of chemotherapeutic agents. In current work, we discovered the novel role of miR-491-3p in ABCB1-mediated multidrug resistance in HCC and revealed the underlying mechanism in which miR-491-3p downregulated the expression of ABCB1 and its transcription factor Sp3 by directly targeting their 3'-UTR. Moreover, overexpressing ABCB1 or Sp3 reversed the sensitivity to chemotherapeutics in Hep3B cells induced by miR-491-3p, confirming miR-491-3p/Sp3/ABCB1 regulatory loop plays an important role in enhancing the drugs sensitivity of HCC. Meanwhile, the discovery of that the expression level of miR-491-3p was inversely correlated with that of ABCB1 and Sp3 in HCC cell lines and clinical samples pointed out the possibility of miR-491-3p in clinical use. In summary, our results reveal a pivotal role of miR-491-3p in the regulation of MDR in HCC, and suggest the potential application of miR-491-3p as a therapeutic strategy for modulating MDR in cancer cells.
Insights
MicroRNA-491-3p resensitizes hepatocellular carcinoma (HCC) cells to chemotherapy by downregulating P-glycoprotein (P-gp/ABCB1). This microRNA offers a potential therapeutic strategy to overcome multidrug resistance in HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hepatocellular carcinoma (HCC) exhibits multidrug resistance (MDR), often linked to P-glycoprotein (P-gp/ABCB1) efflux pump overexpression, reducing chemotherapeutic efficacy.
- Understanding the molecular mechanisms underlying HCC MDR is crucial for developing effective treatment strategies.
Purpose of the Study:
- To investigate the role of miR-491-3p in regulating ABCB1-mediated multidrug resistance in HCC.
- To elucidate the underlying molecular mechanism of miR-491-3p action in HCC MDR.
Main Methods:
- Investigated the direct targeting of ABCB1 and its transcription factor Sp3 by miR-491-3p.
- Utilized Hep3B cells to examine the effects of overexpressing ABCB1 or Sp3 on chemotherapeutic sensitivity induced by miR-491-3p.
- Analyzed the correlation between miR-491-3p, ABCB1, and Sp3 expression in HCC cell lines and clinical samples.
Main Results:
- miR-491-3p was found to downregulate the expression of ABCB1 and Sp3 by directly targeting their 3'-UTR.
- Overexpression of ABCB1 or Sp3 reversed the enhanced sensitivity to chemotherapeutics induced by miR-491-3p in Hep3B cells.
- An inverse correlation was observed between miR-491-3p levels and ABCB1/Sp3 expression in HCC cell lines and clinical samples.
Conclusions:
- miR-491-3p plays a pivotal role in regulating MDR in HCC by targeting the miR-491-3p/Sp3/ABCB1 regulatory loop.
- miR-491-3p demonstrates potential as a therapeutic strategy for modulating MDR in cancer cells, offering a novel approach for HCC treatment.
