TGF-β1 elevates P-gp and BCRP in hepatocellular carcinoma through HOTAIR/miR-145 axis.

ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics ATP Binding Cassette Transporter, Subfamily G, Member 2 / genetics Animals Base Sequence Biological Transport CHO Cells Carcinoma, Hepatocellular / metabolism Cricetulus Drug Resistance, Neoplasm Female HCT116 Cells Hep G2 Cells Humans Imatinib Mesylate / pharmacokinetics Liver Neoplasms / metabolism Male Mice Mice, Knockout MicroRNAs / genetics Neoplasm Proteins / genetics RNA, Long Noncoding / genetics Transforming Growth Factor beta1 / pharmacology

BCRP P-gp TGF-β1 hepatocellular carcinoma miR-145

Journal

Biopharmaceutics & drug disposition

ISSN: 1099-081X

Titre abrégé: Biopharm Drug Dispos

Pays: England

ID NLM: 7911226

Informations de publication

Date de publication:
Feb 2019

Historique:

received: 25 10 2018

revised: 13 01 2019

accepted: 23 01 2019

pubmed: 31 1 2019

medline: 15 6 2019

entrez: 31 1 2019

Statut: ppublish

Résumé

Multidrug resistance (MDR) is common in patients and has been linked to transforming growth factor-β1 (TGF-β1) and overexpression of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), although the molecular mechanisms remain largely unknown. This study aimed to investigate the mechanisms underlying TGF-β1-induced MDR in hepatocellular carcinoma (HCC) cells. It was found that TGF-β1 upregulated HOX transcript antisense RNA (HOTAIR) expression in HCC cells. When drosophila mothers against decapentaplegic 4 (SMAD4) was silenced, HOTAIR expression was accordingly reduced. Meanwhile, miR-145 expression was increased in the case HOTAIR was silenced. If the enhancer of zeste homolog 2 (EZH2) was knocked down using small interfering RNA (siRNA), miR-145 expression was decreased. Then, the regulatory role of miR-145 in P-gp and BCRP expression was explored. The results showed that the expression of P-gp and BCRP protein was suppressed by miR-145 through binding to the 3'-untranslated regions (3'-UTRs) of P-gp and BCRP. In conclusion, our study revealed a novel mechanism explaining TGF-β1-induced MDR in HCC through upregulating P-gp and BCRP via the SMAD4/HOTAIR/miR-145 axis.

Identifiants

DOI: 10.1002/bdd.2172 PMID: 30698830

pubmed: 30698830

doi: 10.1002/bdd.2172

doi:

Substances chimiques

ABCG2 protein, human 0

ATP Binding Cassette Transporter, Subfamily B, Member 1 0

ATP Binding Cassette Transporter, Subfamily G, Member 2 0

HOTAIR long untranslated RNA, human 0

MIRN145 microRNA, human 0

MicroRNAs 0

Neoplasm Proteins 0

RNA, Long Noncoding 0

Transforming Growth Factor beta1 0

Imatinib Mesylate 8A1O1M485B

Types de publication

Journal Article

Langues

eng