Unknown

Dataset Information

0

Complete response of Ctnnb1-mutated tumours to ?-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model.


ABSTRACT: Hepatocellular cancer (HCC) remains a disease of poor prognosis, highlighting the relevance of elucidating key molecular aberrations that may be targeted for novel therapies. Wnt signalling activation, chiefly due to mutations in CTNNB1, have been identified in a major subset of HCC patients. While several in vitro proof of concept studies show the relevance of suppressing Wnt/?-catenin signalling in HCC cells or tumour xenograft models, no study has addressed the impact of ?-catenin inhibition in a relevant murine HCC model driven by Ctnnb1 mutations.We studied the in vivo impact of ?-catenin suppression by locked nucleic acid (LNA) antisense treatment, after establishing Ctnnb1 mutation-driven HCC by diethylnitrosamine and phenobarbital (DEN/PB) administration.The efficacy of LNA directed against ?-catenin vs. scrambled on Wnt signalling was demonstrated in vitro in HCC cells and in vivo in normal mice. The DEN/PB model leads to HCC with Ctnnb1 mutations. A complete therapeutic response in the form of abrogation of HCC was observed after ten treatments of tumour-bearing mice with ?-catenin LNA every 48h as compared to the scrambled control. A decrease in ?-catenin activity, cell proliferation and increased cell death was evident after ?-catenin suppression. No effect of ?-catenin suppression was evident in non-Ctnnb1 mutated HCC, observed after DEN-only administration.Thus, we provide the in vivo proof of concept that ?-catenin suppression in HCC will be of significant therapeutic benefit, provided the tumours display Wnt activation via mechanisms like CTNNB1 mutations.

SUBMITTER: Delgado E 

PROVIDER: S-EPMC4300253 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

Similar Datasets

1000-01-01 | S-EPMC5511151 | BioStudies
2019-01-01 | S-EPMC6826293 | BioStudies
1000-01-01 | S-EPMC5397318 | BioStudies
2012-01-01 | S-EPMC3446854 | BioStudies
2016-01-01 | S-EPMC4615253 | BioStudies
2018-01-01 | S-EPMC6190118 | BioStudies
2020-01-01 | S-EPMC7268324 | BioStudies
2017-01-01 | S-EPMC5371438 | BioStudies
1000-01-01 | S-EPMC6031179 | BioStudies
2018-01-01 | S-EPMC6279049 | BioStudies