Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor
, which ...occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between
LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the
imprint control region that abolishes CTCF insulator activity, resulting in biallelic
expression that mimics increased levels seen with aging-induced LOI. We found that
LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering
deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that
LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways.
.
Ginkgo biloba
extract (GBE) is used in traditional Chinese medicine as a herbal supplement for improving memory. Exposure of B6C3F1/N mice to GBE in a 2-year National Toxicology Program (NTP) ...bioassay resulted in a dose-dependent increase in hepatocellular carcinomas (HCC). To identify key microRNAs that modulate GBE-induced hepatocarcinogenesis, we compared the global miRNA expression profiles in GBE-exposed HCC (GBE-HCC) and spontaneous HCC (SPNT-HCC) with age-matched vehicle control normal livers (CNTL) from B6C3F1/N mice. The number of differentially altered miRNAs in GBE-HCC and SPNT-HCC was 74 (52 up and 22 down) and 33 (15 up and 18 down), respectively. Among the uniquely differentially altered miRNAs in GBE-HCC, miR-31 and one of its predicted targets,
Cdk1
were selected for functional validation. A potential miRNA response element (MRE) in the 3′-untranslated regions (3′-UTR) of
Cdk1
mRNA was revealed by in silico analysis and confirmed by luciferase assays. In mouse hepatoma cell line HEPA-1 cells, we demonstrated an inverse correlation between miR-31 and CDK1 protein levels, but no change in
Cdk1
mRNA levels, suggesting a post-transcriptional effect. Additionally, a set of miRNAs (miRs-411, 300, 127, 134, 409-3p, and 433-3p) that were altered in the GBE-HCCs were also altered in non-tumor liver samples from the 90-day GBE-exposed group compared to the vehicle control group, suggesting that some of these miRNAs could serve as potential biomarkers for GBE exposure or hepatocellular carcinogenesis. These data increase our understanding of miRNA-mediated epigenetic regulation of GBE-mediated hepatocellular carcinogenesis in B6C3F1/N mice.
Abstract Prostate cancer (PCa) is typically found as a multifocal disease suggesting the potential for molecular defects within the morphologically normal tissue. The frequency and spatial extent of ...DNA methylation changes encompassing a potential field defect are unknown. A comparison of non-tumor-associated (NTA) prostate to histologically indistinguishable tumor-associated (TA) prostate tissues detected a distinct profile of DNA methylation alterations (0.2%) using genome-wide DNA arrays based on the Encyclopedia of DNA Elements 18 sequence that tile both gene-rich and poor regions. Hypomethylation (87%) occurred more frequently than hypermethylation (13%). Several of the most significantly altered loci ( CAV1, EVX1, MCF2L , and FGF1 ) were then used as probes to map the extent of these DNA methylation changes in normal tissues from prostates containing cancer. In TA tissues, the extent of methylation was similar both adjacent (2 mm) and at a distance (>1 cm) from tumor foci. These loci were also able to distinguish NTA from TA tissues in a validation set of patient samples. These mapping studies indicate that a spatially widespread epigenetic defect occurs in the peripheral prostate tissues of men who have PCa that may be useful in the detection of this disease.
Throughout history, the utilization of plant products as medicinal remedies has been widespread, with numerous modern drugs finding their origins in the plant kingdom. Taxol, derived from Taxus ...species, stands out as an exceptional and highly potent anticancer medication. In this study, we present a rapid one-pot synthesis method for silver nanoparticles (AgNPs) using the leaves of
Zucca in the presence of sunlight. The synthesized AgNPs were comprehensively characterized using X-ray diffraction, transmission electron microscopy, and HPLC Q-TOF. The AgNPs were further investigated for their antioxidative, anticancer, anti-inflammatory, and antiurolithi properties. The anticancer activity was assessed through a sulforhodamine B assay conducted on the MDA-MB-231 human breast carcinoma cell line and SiHa human cervical cancer cell line. The findings of this study reveal the impressive antioxidative, anticancer, anti-inflammatory, and antiurolithi characteristics exhibited by AgNPs synthesized from leaf extracts. This research highlights an environmentally friendly and cost-effective approach to producing AgNPs by utilizing plant extracts as reducing agents, underscoring the immense potential of natural resources in advancing nanotechnology and its applications.
The purpose of this work is to provide a complete study of the influence of operational parameters of the supercritical carbon dioxide assisted extraction (SC CO2E) on yield of wedelolactone from ...Wedelia calendulacea Less., and to find an optimal combination of factors that maximize the wedelolactone yield. In order to determine the optimal combination of the four factors viz. operating pressure, temperature, modifier concentration and extraction time, a Taguchi experimental design approach was used: four variables (three levels) in L9 orthogonal array. Wedelolactone content was determined using validated HPLC methodology. Optimum extraction conditions were found to be as follows: extraction pressure, 25MPa; temperature, 40°C; modifier concentration, 10% and extraction time, 90min. Optimum extraction conditions demonstrated wedelolactone yield of 8.01±0.34mg/100g W. calendulacea Less. Pressure, temperature and time showed significant (p<0.05) effect on the wedelolactone yield. The supercritical carbon dioxide extraction showed higher selectivity than the conventional Soxhlet assisted extraction method.
Increased oxidative stress and concordant DNA methylation changes are found during aging and in many malignant processes including prostate cancer. Increased oxidative stress has been shown to ...inhibit DNA methyltransferase in in vitro assays, but whether this occurs in vivo is unknown. To generate increased oxidative stress we utilized mice containing mutations in the CuZnSOD (Sod1) gene, a major superoxide dismutase in mammals. Increased 8-hydroxy-2'-deoxyguanosine, an adduct indicating oxidative damage, was found in liver and prostate tissues at 2 and 12 mo Sod1
+/-
mice compared to controls. Prostate tissues from Sod1
+/-
mice demonstrated decreased weight at 2 mo compared to controls, but this difference was not significant at 12 mo. Histologic changes were not seen. Global DNA methylation was significantly decreased at 2 mo in the prostate in Sod1
+/-
mice. 11p15 containing the epigenetically modulated insulin-like growth factor 2 (Igf2) and H19 genes, both which display oncogenic functions, may be particularly sensitive to oxidative stress. CpG island methylation at an intergenic CTCF binding site and the Igf2 P3 promoter was decreased in Sod1 mutants compared to controls. This is the first in vivo study to show that a deficiency of Sod1 leads to a decrease in DNA methylation. These studies indicate that increased oxidative stress, a factor implicated in neoplasia, can induce DNA hypomethylation in prostate tissues.
The response surface methodology using the Box-Behnken design was established to describe supercritical carbon dioxide assisted extraction of phyllanthin from Phyllanthus amarus Schum and Thonn ...leaves prior to HPLC analysis. The effects of extraction pressure, temperature, modifier concentration and extraction time on the yield of phyllanthin were investigated. By solving the regression equation, the optimum conditions were as follows: extraction pressure 23.2 MPa, temperature 40 °C, methanol as modifier at a concentration of 10 % and time 90 min. Under these conditions, the phyllanthin yield was 12.83 ± 0.28 mg g-1, which was in good agreement with the predicted values. Modifier concentration and extraction time showed a significant effect on the phyllanthin yield.
The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs ...arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard.
PDF
