Loss of Thymine DNA Glycosylase Causes Dysregulation of Bile Acid Homeostasis and Hepatocellular Carcinoma

The RNA binding protein human antigen R is a gatekeeper of liver homeostasis

“…Positive alpha‐fetoprotein (AFP) staining (Figure 3G), together with the characteristic absence of reticulin staining (Figure 3H) in the tumor tissues of HuR HepKO mice, further underlined the resemblance to HCC. [ 25,26 ] Hepatic inflammation was increased in HuR‐deficient mice compared to control mice, as assessed histologically (Figure 4A). Flow‐cytometric analysis for immune cell populations in the liver revealed significant increases in the numbers of cluster of differentiation 8–positive (CD8 + ) T cells (CD8 + CD4 − cells), NK1.1 + natural killer (NK) T cells (CD4 − CD8 − NK1.1 + ), and infiltrating macrophages (Gr1 − CD11b + CD11c − MHCII + Ly6c + ) (Figures 4B–G and ).…”

TDG is a novel tumor suppressor of liver malignancies

“…However, a direct role for Tdg as a tumor suppressor has not been formally demonstrated. In our recent Cell Reports publication, 6 we addressed this question using a conditional knockout mouse model of Tdg (Tdg cKO ; Tdg f/-;UBC-creERT2 + ). We observed efficient excision of Tdg in response to tamoxifen.…”

The Role of Thymine DNA Glycosylase in Transcription, Active DNA Demethylation, and Cancer

“…TDG was found to potentiate p53 signaling, which in turn regulates its own expression [52]. TDG was also found to be essential for the expression of several tumor suppressors genes in vitro, such as p15 ink4b , Hic1, Rarβ, and Nr0b2 [29,53,54]. Several conditional Tdg knockout studies performed in mice have since provided support for TDG as a tumor suppressor in vivo [53,55].…”

“…TDG was also found to be essential for the expression of several tumor suppressors genes in vitro, such as p15 ink4b , Hic1, Rarβ, and Nr0b2 [29,53,54]. Several conditional Tdg knockout studies performed in mice have since provided support for TDG as a tumor suppressor in vivo [53,55]. One study demonstrated that intestinalspecific loss of Tdg in Apc Min mice, a well-characterized model of tumor disposition, resulted in a two-fold increase in small intestinal adenomas [55].…”

“…This phenotype was observed predominantly in female mice, suggesting that sexual dimorphism may contribute to cancer incidence in response to Tdg loss. Utilizing a novel conditional Tdg knockout mouse model containing the tamoxifen-inducible Cre-ERT2 to excise Tdg in all tissues in a temporal fashion [53], our lab demonstrated that the conditional deletion of Tdg in adult mice (Tdg cKO ) resulted in the development of late-onset hepatocellular carcinoma (HCC) and hepatoblastoma (HB). Interestingly, a sex bias in HCC incidence in the Tdg cKO mice was observed, with male mice displaying an approximately 2-fold increase in HCC incidence compared to females.…”