Overall, while chronic administration of the model CAR activator NaPB results in both hepatocellular adenoma and carcinoma in the low spontaneous liver tumour incidence C57BL/10 J mouse strain, only 40% of the liver tumours evaluated in this study had β-catenin mutations.
This was confirmed by RT-qPCR of an independent cohort of CTNNB1-mutated HCC and the suppression of the LKB1-related profile upon β-catenin silencing of CTNNB1-mutated human hepatoma cell lines.
Using both human HCC collections and engineered mouse models of liver cancers with AXIN1 mutation or deletion, we defined a common signature of liver tumors mutated for AXIN1 and demonstrate that these tumors occur independently of the activation of the Wnt/β-catenin pathway.
An identical CTNNB1 mutation was identified in the 1996 liver tumor together with a TERT promoter mutation showing that this hepatocellular carcinoma results from the malignant transformation of the initial β-catenin inflammatory adenoma.
These data established Wnt/β-catenin as a novel signal produced by infiltrating macrophages induced by steatosis that promotes growth of tumor progenitor cells, underlying the increased risk of liver tumor development in obese individuals.
Taken together, these data indicate that β-catenin creates a protumorigenic hepatic environment in part by indirectly activating Nrf2 and implicate oxidative stress as a possible driving force for a subset of β-catenin-driven liver tumors in children.
We found that forced overexpression of SKP2, N-RasV12 or ΔN90-β-catenin alone as well as co-expression of SKP2 and ΔN90-β-catenin did not induce liver tumor development.
In summary, a senescence-inducing program was found in hepatocytes with increased β-catenin levels and a positive selection of hepatocytes lacking p16(INK4a), by epigenetic silencing, drives the development of liver tumors in mice with reduced APC expression (Apc(580S) mice).
The cell proliferation was significantly inhibited (up to 95.11 %) by shRNA plus anti-cancer drugs, suggesting that GPC-3 gene should be a potential target for promoting hepatoma cell apoptosis and inhibiting metastasis through the Wnt/β-catenin and Hh singling pathways.
In agreement with transcription level, β-catenin and cyclin D1 proteins are also down-regulated in transient and stable ZNF191 knockdown L02 and hepatoma Hep3B cell lines.
Additionally, core protein increases and stabilizes β-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3β, which contributes to the up-regulation of downstream target genes, such as c-Myc, cyclin D1, WISP2 and CTGF.
The prevalence of tumors in Ctnnb1 KO mice was ∼7-fold higher than in wild-type mice, suggesting an enhancing effect of the gene KO on liver tumor development.
In conclusion, activated β-catenin in single hepatocytes induces a gene expression pattern in hepatocytes which is similar to that of Ctnnb1-mutated mouse liver tumors, but is apparently not sufficient to induce increased cell proliferation.