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Published on: October 21, 2017
Chronic microcystin exposure induces hepatocyte proliferation with increased expression of mitotic and
Shawn P Clark1, Timothy P Ryan, George H Searfoss
1Department of Veterinary Pathobiology, Purdue University, West Lafayette, Indiana, USA. shawn.clark@bms.com
Abstract:
Homozygous p53 deficient knockout mice were used to assess the role of p53 in tumor promotion by the protein phosphatase inhibitor and hepatic tumor promoter microcystin-LR (MCLR). More than 50% of human cancers bear mutations in the p53 gene, and in particular, p53 tumor suppressor gene mutations have been shown to play a major role in hepatocarcinogenesis. Trp53 homozygous (inactivated p53) and age-matched wild-type control mice were assigned to vehicle or MCLR-treated groups. MCLR or saline was administered daily for up to 28 days. RNA from the 28-day study was hybridized onto Mouse Genome GeneChip arrays. Selected RNA from 28 days and earlier time points was also processed for quantitative polymerase chain reaction (PCR). Livers from the 28-day, Trp53-deficient, MCLR group displayed greater hyperplastic and dysplastic changes morphologically and increases in Ki-67 and phosphohistone H3 (mitotic marker) immunoreactivity. Gene-expression analysis revealed significant increases in expression of cell-cycle regulation and cellular proliferation genes in the MCLR-treated, p53-deficient mutant mice compared to controls. These data suggest that regulation of the cell cycle by p53 is important in preventing the proliferative response associated with chronic, sublethal microcystin exposure, and therefore, conclude that p53 plays an important role in MCLR-induced tumor promotion.
Insights
The p53 tumor suppressor gene is crucial in preventing liver cancer promotion by microcystin-LR (MCLR). Inactivated p53 in mice led to increased cell proliferation and tumor development when exposed to MCLR, highlighting p53
Area of Science:
- Hepatocarcinogenesis research
- Molecular toxicology
- Cancer biology
Background:
- Over 50% of human cancers have p53 gene mutations.
- p53 tumor suppressor gene mutations are significant in liver cancer development.
- Microcystin-LR (MCLR) is a protein phosphatase inhibitor and liver tumor promoter.
Purpose of the Study:
- To investigate the role of p53 in tumor promotion by MCLR.
- To determine if p53 regulates the cellular response to MCLR exposure.
- To assess the impact of p53 deficiency on MCLR-induced hepatocarcinogenesis.
Main Methods:
- Utilized homozygous p53 deficient (Trp53) and wild-type mice.
- Administered MCLR or saline daily for up to 28 days.
- Analyzed liver tissue using gene expression arrays, quantitative PCR, and immunohistochemistry for proliferation markers (Ki-67, phosphohistone H3).
Main Results:
- p53-deficient mice exposed to MCLR showed increased hyperplastic and dysplastic liver changes.
- Significant increases in cell-cycle regulation and proliferation gene expression were observed in MCLR-treated, p53-deficient mice.
- Elevated Ki-67 and phosphohistone H3 immunoreactivity indicated higher cell proliferation in p53-deficient livers.
Conclusions:
- p53's regulation of the cell cycle is vital in preventing cellular proliferation from chronic, sublethal microcystin exposure.
- p53 plays a critical role in the tumor promotion process induced by MCLR.
- Inactivation of p53 exacerbates MCLR-induced liver damage and promotes tumor development.
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