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


Qiao Y., Wang J., Karagoz E., Liang B., Song X., Shang R., ...Daha Fazla

HEPATOLOGY, cilt.70, sa.6, ss.2003-2017, 2019 (SCI İndekslerine Giren Dergi) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 70 Konu: 6
  • Basım Tarihi: 2019
  • Doi Numarası: 10.1002/hep.30556
  • Dergi Adı: HEPATOLOGY
  • Sayfa Sayıları: ss.2003-2017

Özet

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.