Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib.
Animals
Antineoplastic Agents
/ pharmacology
CHO Cells
Carcinoma, Hepatocellular
/ drug therapy
Cell Proliferation
/ drug effects
Cricetulus
Drug Screening Assays, Antitumor
Epigenesis, Genetic
/ drug effects
Gene Expression Profiling
Gene Silencing
/ drug effects
HEK293 Cells
Hep G2 Cells
Humans
Liver Neoplasms
/ drug therapy
Liver Neoplasms, Experimental
/ drug therapy
Male
Octamer Transcription Factor-1
/ antagonists & inhibitors
RNA, Messenger
/ antagonists & inhibitors
Rats
Rats, Wistar
Sorafenib
/ pharmacology
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
09
05
2018
revised:
14
11
2018
accepted:
27
11
2018
pubmed:
29
12
2018
medline:
9
4
2020
entrez:
29
12
2018
Statut:
ppublish
Résumé
The expression of the human organic cation transporter-1 (hOCT1, gene SLC22A1) is reduced in hepatocellular carcinoma (HCC). The molecular bases of this reduction and its relationship with the poor response of HCC to sorafenib were investigated. HCC transcriptomes from 366 samples available at TCGA were analysed. Alternative splicing was determined by RT-PCR. The role of miRNAs in SLC22A1 downregulation was investigated. Expression of Oct1 was measured in rodent HCC models (spontaneously generated in Fxr hOCT1 overexpression enhanced sorafenib, but not regorafenib, quinine-inhibitable uptake by hepatoma cells. In rodent HCC, Oct1 was downregulated, which was accompanied by impaired sorafenib uptake. In mice with s.c.-implanted HCC, sorafenib inhibited the growth of hOCT1 overexpressing tumours. In human HCC, hOCT1 expression was inversely correlated with SLC22A1 promoter methylation, whereas demethylation with decitabine enhanced hOCT1 expression in hepatoma cells. Increased proportion of aberrant hOCT1 mRNA variants was found in HCC samples. In silico analysis identified six miRNAs as candidates to target hOCT1 mRNA. When overexpressed in HepG2 cells a significant hOCT1 mRNA decay was induced by hsa-miR-330 and hsa-miR-1468. Analysis of 39 paired tumour/adjacent samples from TCGA revealed that hsa-mir-330 was consistently upregulated in HCC. Impaired hOCT1 expression/function in HCC, in part due to epigenetic modifications, plays an important role in the poor pharmacological response of this cancer to sorafenib.
Sections du résumé
BACKGROUND AND PURPOSE
The expression of the human organic cation transporter-1 (hOCT1, gene SLC22A1) is reduced in hepatocellular carcinoma (HCC). The molecular bases of this reduction and its relationship with the poor response of HCC to sorafenib were investigated.
EXPERIMENTAL APPROACH
HCC transcriptomes from 366 samples available at TCGA were analysed. Alternative splicing was determined by RT-PCR. The role of miRNAs in SLC22A1 downregulation was investigated. Expression of Oct1 was measured in rodent HCC models (spontaneously generated in Fxr
KEY RESULTS
hOCT1 overexpression enhanced sorafenib, but not regorafenib, quinine-inhibitable uptake by hepatoma cells. In rodent HCC, Oct1 was downregulated, which was accompanied by impaired sorafenib uptake. In mice with s.c.-implanted HCC, sorafenib inhibited the growth of hOCT1 overexpressing tumours. In human HCC, hOCT1 expression was inversely correlated with SLC22A1 promoter methylation, whereas demethylation with decitabine enhanced hOCT1 expression in hepatoma cells. Increased proportion of aberrant hOCT1 mRNA variants was found in HCC samples. In silico analysis identified six miRNAs as candidates to target hOCT1 mRNA. When overexpressed in HepG2 cells a significant hOCT1 mRNA decay was induced by hsa-miR-330 and hsa-miR-1468. Analysis of 39 paired tumour/adjacent samples from TCGA revealed that hsa-mir-330 was consistently upregulated in HCC.
CONCLUSION AND IMPLICATIONS
Impaired hOCT1 expression/function in HCC, in part due to epigenetic modifications, plays an important role in the poor pharmacological response of this cancer to sorafenib.
Identifiants
pubmed: 30592786
doi: 10.1111/bph.14563
pmc: PMC6393231
doi:
Substances chimiques
Antineoplastic Agents
0
Octamer Transcription Factor-1
0
POU2F1 protein, human
0
RNA, Messenger
0
Sorafenib
9ZOQ3TZI87
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
787-800Informations de copyright
© 2018 The British Pharmacological Society.
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