Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact β-Catenin but Not Notch Cascade in Mice.

Yu Qiao, Jingxiao Wang, Eylul Karagoz, Binyong Liang, Xinhua Song, Runze Shang, Katja Evert, Meng Xu, Li Che, Matthias Evert, Diego F Calvisi, Junyan Tao, Bruce Wang, Satdarshan P Monga, Xin Chen

Hepatology (Baltimore, Md.) 2019 Dec

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Inactivating mutations of axis inhibition protein 1 (AXIN1), a negative regulator of the Wnt/β-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/β-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/∆N90-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 with corresponding lesions from c-Met/∆N90-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, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-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 β-Catenin signaling-dependent but Notch cascade-independent way. © 2019 by the American Association for the Study of Liver Diseases.

Citation

Yu Qiao, Jingxiao Wang, Eylul Karagoz, Binyong Liang, Xinhua Song, Runze Shang, Katja Evert, Meng Xu, Li Che, Matthias Evert, Diego F Calvisi, Junyan Tao, Bruce Wang, Satdarshan P Monga, Xin Chen. Axis inhibition protein 1 (Axin1) Deletion-Induced Hepatocarcinogenesis Requires Intact β-Catenin but Not Notch Cascade in Mice. Hepatology (Baltimore, Md.). 2019 Dec;70(6):2003-2017