The miR-491-3p/Sp3/ABCB1 axis attenuates multidrug resistance of hepatocellular carcinoma

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 chemotherapeuti...

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Bibliographic Details
Published in:Cancer letters 2017-11, Vol.408, p.102-111
Main Authors: Zhao, Yang, Qi, Xinming, Chen, Jing, Wei, Wenxin, Yu, Cunzhi, Yan, Hong, Pu, Mengfan, Li, Yu, Miao, Lingling, Li, Chunzhu, Ren, Jin
Format: Article
Language:English
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3' Untranslated regions
ABCB1
Antibiotics
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
ATP Binding Cassette Transporter, Sub-Family B - genetics
ATP Binding Cassette Transporter, Sub-Family B - metabolism
Cancer therapies
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - metabolism
Carcinoma, Hepatocellular - pathology
Cell Proliferation - drug effects
Chemotherapy
Drug resistance
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Fluorides
Gastric cancer
Gene expression
Gene Expression Regulation, Neoplastic - drug effects
Hepatocellular carcinoma
Humans
Liver cancer
Liver Neoplasms - drug therapy
Liver Neoplasms - metabolism
Liver Neoplasms - pathology
MicroRNAs
MicroRNAs - genetics
miR-491-3p
Multidrug resistance
Multidrug resistant organisms
P-Glycoprotein
Penicillin
Plasmids
Rodents
Sensitivity
Sp3
Sp3 Transcription Factor - genetics
Sp3 Transcription Factor - metabolism
Transcription factors
Tumor Cells, Cultured
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Summary: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. •MiR-491-3p inhibits both post-transcriptional level and transcriptional level of ABCB1.•The miR-491-3p/ABCB1/Sp3 regulatory loop increases the sensitivity of HCC cells to chemotherapeutics.•New therapeutic strategies targeted on the miR-491-3p/ABCB1/Sp3 axis may enhance the efficacy of chemotherapy against HCC.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2017.08.027