التفاصيل البيبلوغرافية
| العنوان: |
Complete response of Ctnnb1-mutated tumours to β-catenin suppression by locked nucleic acid antisense in a mouse hepatocarcinogenesis model. |
| المؤلفون: |
Delgado, Evan1, Okabe, Hirohisa1, Preziosi, Morgan1, Russell, Jacquelyn Olivia1, Alvarado, Tamara Feliciano1, Oertel, Michael1, Nejak-Bowen, Kari Nichole1, Zhang, Yixian2, Monga, Satdarshan P.S.1,3 smonga@pitt.edu |
| المصدر: |
Journal of Hepatology. Feb2015, Vol. 62 Issue 2, p380-387. 8p. |
| مصطلحات موضوعية: |
*LIVER cancer, *GENETIC mutation, *CATENINS, *IMMUNOSUPPRESSION, *ANTISENSE nucleic acids, *LABORATORY mice, *PROGNOSIS |
| مستخلص: |
Background & Aims 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/β-catenin signalling in HCC cells or tumour xenograft models, no study has addressed the impact of β-catenin inhibition in a relevant murine HCC model driven by Ctnnb1 mutations. Methods We studied the in vivo impact of β-catenin suppression by locked nucleic acid (LNA) antisense treatment, after establishing Ctnnb1 mutation-driven HCC by diethylnitrosamine and phenobarbital (DEN/PB) administration. Results The efficacy of LNA directed against β-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 β-catenin LNA every 48 h as compared to the scrambled control. A decrease in β-catenin activity, cell proliferation and increased cell death was evident after β-catenin suppression. No effect of β-catenin suppression was evident in non- Ctnnb1 mutated HCC, observed after DEN-only administration. Conclusions Thus, we provide the in vivo proof of concept that β-catenin suppression in HCC will be of significant therapeutic benefit, provided the tumours display Wnt activation via mechanisms like CTNNB1 mutations. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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