Tumor-promoting cyanotoxin microcystin-LR does not induce procarcinogenic events in adult human liver stem cells
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
29534881
DOI
10.1016/j.taap.2018.03.011
PII: S0041-008X(18)30089-9
Knihovny.cz E-resources
- Keywords
- Adult liver stem cells, HL1-hT1, Liver tumor-promotion, Microcystin-LR, Multidrug resistance proteins, OATP,
- MeSH
- Apoptosis drug effects physiology MeSH
- Adult Stem Cells drug effects metabolism MeSH
- Hepatocytes drug effects metabolism MeSH
- Enzyme Inhibitors toxicity MeSH
- Liver cytology drug effects metabolism MeSH
- Carcinogens toxicity MeSH
- Humans MeSH
- Microcystins toxicity MeSH
- Marine Toxins MeSH
- Cell Line, Transformed MeSH
- Cell Survival drug effects physiology MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- cyanoginosin LR MeSH Browser
- Enzyme Inhibitors MeSH
- Carcinogens MeSH
- Microcystins MeSH
- Marine Toxins MeSH
HL1-hT1 cell line represents adult human liver stem cells (LSCs) immortalized with human telomerase reverse transcriptase. In this study, HL1-hT1 cells were found to express mesenchymal markers (vimentin, CD73, CD90/THY-1 and CD105) and an early hepatic endoderm marker FOXA2, while not expressing hepatic progenitor (HNF4A, LGR5, α-fetoprotein) or differentiated hepatocyte markers (albumin, transthyretin, connexin 32). In response to microcystin-LR (MC-LR), a time- and concentration-dependent formation of MC-positive protein bands in HL1-hT1 cells was observed. Cellular accumulation of MC-LR occurred most likely via mechanisms independent on organic anion transporting polypeptides (OATPs) or multidrug resistance (MDR) proteins, as indicated (a) by a gene expression analysis of 11 human OATP genes and 4 major MDR genes (MDR1/P-glycoprotein, MRP1, MRP2 and BCRP); (b) by non-significant effects of OATP or MDR1 inhibitors on MC-LR uptake. Accumulation of MC-positive protein bands in HL1-hT1 cells was associated neither with alterations of cell viability and growth, dysregulations of ERK1/2 and p38 kinases, reactive oxygen species formation, induction of double-stranded DNA breaks nor modulations of stress-inducible genes (ATF3, HSP5). It suggests that LSCs might have a selective, MDR1-independent, survival advantage and higher tolerance towards MC-induced cytotoxic, genotoxic or cancer-related events than differentiated adult hepatocytes, fetal hepatocyte or malignant liver cell lines. HL1-hT1 cells provide a valuable in vitro tool for studying effects of toxicants and pharmaceuticals on LSCs, whose important role in the development of chronic toxicities and liver diseases is being increasingly recognized.
References provided by Crossref.org
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