Epigenetic events involved in organic cation transporter 1-dependent impaired response of hepatocellular carcinoma to sorafenib
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Ruba Al-Abdulla, Elisa Lozano, Rocio I R Macias, Maria J Monte, Oscar Briz, Colm J O'Rourke, Maria A Serrano, Jesus M Banales, Matias A Avila, Maria L Martinez-Chantar, Andreas Geier, Jesper B Andersen, Jose J G Marin
BACKGROUND AND PURPOSE: In hepatocellular carcinoma (HCC), the expression of the human organic cation transporter-1 (hOCT1, gene SLC22A1) is reduced. The molecular bases of this phenotypic characteristic and the relationship with the poor response of HCC to sorafenib were investigated. EXPERIMENTAL APPROACH AND KEY RESULTS: hOCT1 over-expression in human hepatoma cells (HuH7 and HepG2) enhanced sorafenib, but not regorafenib, uptake in a quinine sensitive manner. The analysis of HCC transcriptomes (TCGA, n=366) showed reduced hOCT1 mRNA, which was inversely correlated with SLC22A1 promoter methylation. The demethylating agent decitabine enhanced hOCT1 expression in hepatoma cells. In clinical samples of HCC, determination of total and alternatively spliced hOCT1 mRNA transcripts revealed enhanced proportion of aberrant short variants. Six miRNAs highly expressed in HCC (TCGA) were identified by in silico analysis as candidates to target hOCT1 mRNA. When overexpressed in HepG2 cells a significant hOCT1 mRNA decay was induced only by hsa-mir-330 and hsa-mir-1468. Analysis of 39 paired samples from TCGA revealed that only hsa-mir-330 was consistently up-regulated in HCC. The expression of the orthologues mOct1 and rOct1 was reduced in spontaneously generated HCC in Fxr-/- mice and chemically induced HCC in rats, respectively. This resulted in impaired uptake of sorafenib (HPLC-MS/MS). In mice, sorafenib treatment efficiently inhibited the growth of subcutaneously implanted tumours only if these were generated by cells over-expressing hOCT1.
CONCLUSION AND IMPLICATIONS: Impaired hOCT1 expression/function in HCC, which is due in part to epigenetic modifications, plays an important role in the poor pharmacological response of this cancer to sorafenib.
|Journal||British Journal of Pharmacology|
|Number of pages||14|
|Publication status||Published - 2019|
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