Qiao, Yu and Wang, Jingxiao and Karagoz, Eylul and Liang, Binyong and Song, Xinhua and Shang, Runze and Evert, Katja and Xu, Meng and Che, Li and Evert, Matthias and Calvisi, Diego F. and Tao, Junyan and Wang, Bruce and Monga, Satdarshan P. and Chen, Xin (2019) Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact beta-Catenin but Not Notch Cascade in Mice. HEPATOLOGY, 70 (6). pp. 2003-2017. ISSN 0270-9139, 1527-3350
Full text not available from this repository. (Request a copy)Abstract
Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/beta-Catenin cascade, are among the common genetic events in human hepatocellular carcinoma (HCC), affecting approximately 10% of cases. In the present manuscript, we sought to define the genetic crosstalk between Axin1 mutants and Wnt/beta-catenin as well as Notch signaling cascades along hepatocarcinogenesis. We discovered that c-MET activation and AXIN1 mutations occur concomitantly in ~3%-5% of human HCC samples. Subsequently, we generated a murine HCC model by means of CRISPR/Cas9-based gene deletion of Axin1 (sgAxin1) in combination with transposon-based expression of c-Met in the mouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and HCCs induced by c-Met/ increment N90-beta-Catenin revealed activation of the Wnt/beta-Catenin and Notch signaling in c-Met/sgAxin1 HCCs. However, only a few of the canonical Wnt/beta-Catenin target genes were induced in c-Met/sgAxin1 HCC when compared with corresponding lesions from c-Met/ increment N90-beta-Catenin mice. To study whether endogenous beta-Catenin is required for c-Met/sgAxin1-driven HCC development, we expressed c-Met/sgAxin1 in liver-specific Ctnnb1 null mice, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of beta-Catenin strongly inhibited cell proliferation. In striking contrast, blocking the Notch cascade through expression of either the dominant negative form of the recombinant signal-binding protein for immunoglobulin kappa J region (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 beta-Catenin signaling-dependent but Notch cascade-independent way.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HEPATOCELLULAR CARCINOMAS; MET; COEXPRESSION; SUBSET; TARGET; MOUSE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 25 Mar 2020 06:28 |
| Last Modified: | 06 Apr 2020 05:52 |
| URI: | https://pred.uni-regensburg.de/id/eprint/25752 |
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