AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation

Abstract

Liver cancer has a poor prognosis. Defining the molecular pathways involved is important for developing new therapeutic approaches. The Wnt/β-catenin pathway is the most frequently deregulated pathway in hepatocellular carcinoma (HCC). Mutations of AXIN1, a member of this pathway, represent about 10% of HCC mutations. 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.

Axis inhibition protein 1 (Axin1) Deletion–Induced Hepatocarcinogenesis Requires Intact β‐Catenin but Not Notch Cascade in Mice

“…A previous study suggests that Notch pathway is activated in AXIN1 mutant human HCC . Consistent with this report, our global gene expression analysis revealed the activation of Notch signaling in c‐Met/sgAxin1 HCC samples (Fig.…”

“…Intriguingly, several studies revealed the lack of expression of liver‐specific Wnt/β‐Catenin target genes, such as GS, in human and mouse HCCs harboring AXIN1 mutations . Using gene expression analysis, a recent study by Abitbol et al suggested that CTNNB1 mutant human HCCs showed strong or weak Wnt/β‐Catenin activation, whereas more than 70% of AXIN1 mutant HCCs belonged to the “no activation” subgroup . All these data suggest that AXIN1 might function through Wnt/β‐Catenin‐independent mechanisms along hepatocarcinogenesis.…”

“…In line with this hypothesis, based on global gene expression patterns, Aritbol et al recently showed that most AXIN1 ‐mutated human HCCs exhibit no activation of β‐Catenin. Gene expression profile analysis suggests rather the enrichment of a Notch signature in AXIN1 mutant HCC samples …”

β-catenin-activated hepatocellular carcinomas are addicted to fatty acids

“…Axin1 deletion does not lead to β-catenin activation in these tumours24 (online supplementary figure SI1D). Axin1 -HCC exhibited the Warburg effect, with decreased glucose oxidation and increased lactate production (online supplementary figure SI2A).…”

“…We experimentally validated these data by characterising the metabolic reprogramming of tumours developed in a model in which HCC is induced following the deletion of Axin1 in hepatocytes, called Axin1 -HCC 24 . Axin1 deletion does not lead to β-catenin activation in these tumours24 (online supplementary figure SI1D).…”