Diethylnitrosamine enhances hepatic tumorigenic pathways in mice fed with high fat diet (Hfd)

Abstract

Obesity has been implicated in the genesis of metabolic syndromes including insulin resistance and Type 2 Diabetes Mellitus (T2DM). Given the association between T2DM and the risk of hepatocellular carcinoma (HCC), our specific goal was to determine whether the liver of HFD-induced T2DM mice is more sensitive to the carcinogen diethylnitrosamine (DEN), due to a modification of the molecular pathways implicated in the early stages of HCC pathogenesis. C57BL/6 male mice (five-week-old) were divided into 4 groups: C, C+DEN, HFD and HFD+DEN. Mice were euthanized twentyfive weeks after DEN-injection. Livers of HDF-fed mice showed a higher proliferative index than Control groups. In line with this, HFD groups showed an increase of nuclear β-catenin, and interestingly, DEN treatment led to a slight increase in the expression of this protein in HFD group. Based on these results, and to confirm this effect, we analyzed β-catenin target genes, finding that DEN treatment in HFD group led to a significant increase of Vegf, c-myc, c-jun and cyclin D1 expression levels. According to our results, the expression of TCF4 showed to be significantly increased in HFD+DEN vs. HFD. In this regard, the β-catenin/TCF4 complex enhanced its association with pSmads 2/3, as we observed an increase of nuclear Smads expression in HFD+DEN, suggesting a possible role of TGF-β1/Smads signaling pathway in this phenomenon. Our results show that the liver of HFD fed model that resembles early T2DM pathology in mice, is more sensitive to DEN, by inducing both Wnt/β-catenin and TGF β1/Smads tumorigenic pathways.

Effect of Codonopsis pilosula Polysaccharides on the Growth and Motility of Hepatocellular Carcinoma HepG2 Cells by Regulating β-Catenin/TCF4 Pathway

“…Upon activation, β-catenin translocates into the nucleus to competitively bind with TCF4 to form β-catenin/TCF4 complex. The complex then activates downstream transcription factors of TCF4, such as cycD and c-Myc, which ultimately leads to cell abnormalities, proliferation, and tumorigenesis [18,19]. Studies have shown that abnormal activation of the TCF4 target gene by Wnt signaling can promote malignant transformation of colorectal cancer [20], and downregulation of the Wnt/β-catenin signaling pathway can inhibit epithelial-mesenchymal transition in nonsmall cell lung cancer [21].…”

Hepatic circadian and differentiation factors control liver susceptibility for fatty liver disease and tumorigenesis

“…6,11 Based on the reduced lipid deposition in BHLivDKO mice, we examined whether the elimination of BMAL1 and HNF4α together was protective in the context of HCC. Using Hnf4a individual knockout mice (H4LivKO) as positive controls, we used DEN injection followed by HFD feeding to induce HCC, a combination of insults that has been shown to accelerate the growth of HCC 53,54 (Figure 2A). WT male and female mice were treated with DEN at day 15 and injected with tamoxifen for 5 days starting at 8 weeks of age.…”

Utility of Human Relevant Preclinical Animal Models in Navigating NAFLD to MAFLD Paradigm

“…In MAFLD-HCC models, DEN is injected intraperitoneally into rodent models fed a HFD to induce HCC. Interestingly, it was reported that under a HFD background, HCC, inflammation, and fibrosis induced by DEN are exacerbated [ 292 , 293 ]. However, in these models, NASH, fibrosis is absent and is hence unable to capture the sequelae of MAFLD progression and consequently NASH-driven HCC [ 294 ].…”