Z Gastroenterol 2019; 57(01): e60-e61
DOI: 10.1055/s-0038-1677207
4. Tumors
Georg Thieme Verlag KG Stuttgart · New York

Loss of Axin1 induced hepatocarcinogenesis requires intact β-Catenin but not Notch cascade in mice

K Evert
1   Universität Regensburg, Institut für Pathologie, Regensburg, Germany
,
Y Qiao
2   Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
J Wang
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
4   School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China
,
E Karagoz
5   Department of Medicine and Liver Center, University of California, San Francisco, CA, USA
6   Acibadem Mehmet Ali Aydinlar University, School of Medicine, Istanbul, Turkey
,
X Song
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
7   Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China
,
M Xu
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
8   Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, PR China
,
L Che
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
J Tao
9   Department of Pathology, University of Pittsburgh School of Medicine, and Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania, USA
,
B Wang
5   Department of Medicine and Liver Center, University of California, San Francisco, CA, USA
,
SP Monga
9   Department of Pathology, University of Pittsburgh School of Medicine, and Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania, USA
,
X Chen
3   Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
,
M Evert
1   Universität Regensburg, Institut für Pathologie, Regensburg, Germany
,
DF Calvisi
1   Universität Regensburg, Institut für Pathologie, Regensburg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

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Background:

Inactivating mutations of Axin1 are among the common genetic events in human hepatocellular carcinoma (HCC), affecting around 10% of cases. Axin1 negatively regulates Wnt/β-Catenin cascade by facilitating b-catenin degradation. However, in human HCC, whether inactivation of Axin1 induces the Wnt/β-Catenin signaling remains controversial.

Methods:

To address this issue, we generated a murine HCC model via CRISPR/Cas9 based gene deletion of Axin1 (sgAxin1) in combination with transposon-based overexpression of c-Met in the mouse liver (c-Met/sgAxin1). This model was than compared to c-Met/ΔN90-β-Catenin mice which were generated before.

Results:

Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1 as well as HCCs induced by c-Met/ΔN90-β-Catenin revealed activation of the Wnt/β-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/β-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared to corresponding lesions from c-Met/ΔN90-β-Catenin mice. To study whether endogenous β-Catenin is required for c-Met/sgAxin1 driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, whichcompletely prevented HCC development. Consistently, in Axin1 mutant human HCC cell lines, silencing of β-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade via expression of either the dominant negative form of RBP-J or the ablation of Notch2, did not significantly affect c-Met/sgAxin1-driven hepatocarcinogenesis.

Conclusion:

We demonstrated here that loss of Axin1 cooperates with c-Met to induce HCC in mice, in a β-Catenin signaling dependent but Notch cascade independent way.