Genome-wide promoter DNA methylation profiling of hepatocellular carcinomas arising either spontaneously or due to chronic exposure to Ginkgo biloba extract (GBE) in B6C3F1/N mice

Abstract

Epigenetic modifications, such as DNA methylation, play an important role in carcinogenesis. In a recent NTP study, chronic exposure of B6C3F1/N mice to Ginkgo biloba extract (GBE) resulted in a high incidence of hepatocellular carcinomas (HCC). Genome-wide promoter methylation profiling on GBE-exposed HCC (2000 mg/kg group), spontaneous HCC (vehicle-control group), and age-matched vehicle control liver was performed to identify differentially methylated genes in GBE-exposed HCC and spontaneous HCC. DNA methylation alterations were correlated to the corresponding global gene expression changes. Compared to control liver, 1296 gene promoters (719 hypermethylated, 577 hypomethylated) in GBE-exposed HCC and 738 (427 hypermethylated, 311 hypomethylated) gene promoters in spontaneous HCC were significantly differentially methylated, suggesting an impact of methylation on GBE-exposed HCC. Differential methylation of promoter regions in relevant cancer genes (cMyc, Spry2, Dusp5) and their corresponding differential gene expression was validated by quantitative pyrosequencing and qRT-PCR, respectively. In conclusion, we have identified differentially methylated promoter regions of relevant cancer genes altered in GBE-exposed HCC compared to spontaneous HCC. Further study of unique sets of differentially methylated genes in chemical-exposed mouse HCC could potentially be used to differentiate treatment-related tumors from spontaneous-tumors in cancer bioassays and provide additional understanding of the underlying epigenetic mechanisms of chemical carcinogenesis.

Procarcinogenic effect of Ginkgo biloba L. extract in a hepatocarcinogenesis model

“…In addition, the increase in the AST/ALT ratio indicates a poor prognosis since it is associated with an increase in tumor size. Therefore, the results found in this study, where an increase in both transaminases is observed, with an AST>ALT ratio, suggests that the administration of EGb could be causing liver damage greater than that of carcinogenic compounds, favoring the development of carcinogenesis, as previously reported [5], which requires further investigation, so, should take its consumption with caution.…”

“…However, recent studies have shown that it can increase the incidence of different types of cancer, including HCC [5].…”

Overexpression SPRY2 Suppresses Esophageal Squamous Cell Carcinoma Progression Via Inactivation of ERK/AKT Signaling

“…Growing evidence has mainly implied that Sprouty2 (SPRY2) as a tumor suppressor in many solid tumors, which can promote tumor cells apoptosis and inhibit their proliferation, invasion and migration ability (Sun et al, 2020;Schumacher et al, 2021). In many instances, downregulation of SPRY2 has been observed in prostate (Samadaian et al, 2018), liver (Kovi et al, 2019), lung (Yawut et al, 2020), and pancreatic cancer (Li et al, 2022), and also has been found to influence EMT process in gastric (Li et al, 2021). However, this finding is not uniformly observed across all cancer cell.…”