Molecular analysis of the Axin1 and Axin2 genes in hepatocellular carcinoma models

Zverev, Matthew 2023. Molecular analysis of the Axin1 and Axin2 genes in hepatocellular carcinoma models. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Summary Aberrant Wnt/β-catenin signalling is frequently implicated in hepatocellular carcinoma (HCC) pathogenesis. AXIN1, a key component of the β-catenin destruction complex, plays a critical role in regulating Wnt/β-catenin signalling. Mutations of AXIN1 in HCC form a highly proliferative subset of tumours that are genomically unstable and clinically aggressive but lack a clear Wnt/β-catenin transcriptional signature. A previous study in this lab showed that conditional deletion of Axin1 in the liver led to the late onset emergence of HCC that shared many similarities to those observed in the human disease. One possible explanation for the lack of a clear strong Wnt/β-catenin signature is that the Axin1 homologue, Axin2, which is also a Wnt/β- Catenin transcriptional target, partially rescues Axin1 loss. Utilizing a floxed Axin2 allele developed in this lab, this doctoral thesis aims to investigate the role of Axin1 and Axin2 using in vivo and in vitro liver models. The results in this thesis show that the loss of Axin2 exacerbated Axin1 dependent tumourigenesis. Surprisingly and by contrast with the loss of APC or mutation of β-catenin, combined acute loss of Axin1 and Axin2 did not activate hepatic Wnt/β-catenin signalling. Instead, additional deletion of Axin2 appeared to attenuate some of the effects of Axin1 deletion. This brought into question whether the Axin alleles used were truly null and led us to attempt to generate definitive Axin nulls in ES cells. Additionally, we used bile duct derived liver (BD) organoids to study the deletion of Axin in vitro to study specific cellular and molecular processes in a controlled environment in which deletion can be observed in real time. When grown in BD organoid differentiation conditions that promote hepatocyte and biliary differentiation, Axin deletion induced significant increases in Wnt/β-catenin signalling, particularly in double Axin1 and Axin2 deleted organoids. The data obtained from this study provides valuable insights into the context dependent functional significance of Axin1 and Axin2 function that has implication for using Axin regulators as therapeutic targets in HCC.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	7 March 2024
Last Modified:	07 Mar 2024 12:02
URI:	https://orca.cardiff.ac.uk/id/eprint/166962

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