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已发表论文
MicroRNA-140-3p 通过靶向孕烯醇酮X受体来增强肝癌细胞对索拉非尼的敏感性
Authors Li J, Zhao J, Wang H, Li X, Liu A, Qin Q, Li B
Received 8 July 2018
Accepted for publication 1 August 2018
Published 17 September 2018 Volume 2018:11 Pages 5885—5894
DOI https://doi.org/10.2147/OTT.S179509
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Colin Mak
Peer reviewer comments 2
Editor who approved publication: Dr Takuya Aoki
Background: Pregnane X
receptor (PXR), which is a member of the nuclear receptor protein family
(nuclear receptor subfamily 1 group I member 2 [NR 1I2]), mediates the
drug-resistance in the hepatocellular carcinoma (HCC) via enhancing the
expression of drug-resistance-related genes which accelerate the clearance of
antitumor drugs, eg, sorafenib. However, there are few reports on miRNA
targeting PXR participating in the epigenetic regulation of PXR in HCC cells.
Materials and methods: TargetScan 7.2, an online method, was used to predict the miRNAs potentially targeting PXR. The expression of PXR and PXR downstream genes was detected by quantitative real-time PCR (qPCR) and Western blot. The clearance of sorafenib in HCC cells was monitored by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). The effects of miRNA on sorafenib’s efficacy were examined by in vitro methods, eg, MTT, and in vivo methods, eg, subcutaneous or intrahepatic tumor model.
Results: By virtual screening, we identified that miR-140-3p possibly targets PXR and then confirmed that the overexpression of miR-140-3p via lentiviral particles inhibited the expression of PXR in HCC cells. The downregulation of PXR’s expression by miR-140-3p led to the reduction of PXR downstream genes’ expression, which finally resulted in the decelerating clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. The effect of miR-140-3p could not modulate the expression of mutated PXR and the effect of miR-140-3p could also be inhibited by miR-140-3p’s inhibitor. Moreover, miR-140-3p enhanced the antitumor effect of sorafenib in both the subcutaneous and intrahepatic HCC tumor models.
Conclusion: Our study suggests that targeting PXR by miR-140-3p is a promising strategy for enhancing sorafenib’s efficacy during HCC treatment.
Keywords: hepatocellular carcinoma, microRNA, pregnenolone X receptor, sorafenib
Materials and methods: TargetScan 7.2, an online method, was used to predict the miRNAs potentially targeting PXR. The expression of PXR and PXR downstream genes was detected by quantitative real-time PCR (qPCR) and Western blot. The clearance of sorafenib in HCC cells was monitored by liquid chromatograph-mass spectrometer/mass spectrometer (LC-MS/MS). The effects of miRNA on sorafenib’s efficacy were examined by in vitro methods, eg, MTT, and in vivo methods, eg, subcutaneous or intrahepatic tumor model.
Results: By virtual screening, we identified that miR-140-3p possibly targets PXR and then confirmed that the overexpression of miR-140-3p via lentiviral particles inhibited the expression of PXR in HCC cells. The downregulation of PXR’s expression by miR-140-3p led to the reduction of PXR downstream genes’ expression, which finally resulted in the decelerating clearance of sorafenib in HCC cells and enhanced the sensitivity of HCC cells to sorafenib. The effect of miR-140-3p could not modulate the expression of mutated PXR and the effect of miR-140-3p could also be inhibited by miR-140-3p’s inhibitor. Moreover, miR-140-3p enhanced the antitumor effect of sorafenib in both the subcutaneous and intrahepatic HCC tumor models.
Conclusion: Our study suggests that targeting PXR by miR-140-3p is a promising strategy for enhancing sorafenib’s efficacy during HCC treatment.
Keywords: hepatocellular carcinoma, microRNA, pregnenolone X receptor, sorafenib
