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

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          Abstract

          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 ouse liver (c-Met/sgAxin1). Global gene expression analysis of mouse normal liver, HCCs induced by c-Met/sgAxin1, and 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 with 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, which completely prevented HCC development. Consistently, in AXIN1 mutant or null human HCC cell lines, silencing of β-Catenin strongly inhibited cell prolif-eration. 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.

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          Author and article information

          Journal
          8302946
          4093
          Hepatology
          Hepatology
          Hepatology (Baltimore, Md.)
          0270-9139
          1527-3350
          5 April 2020
          11 April 2019
          December 2019
          01 December 2020
          : 70
          : 6
          : 2003-2017
          Affiliations
          [1 ]Department of Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China;
          [2 ]Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA;
          [3 ]School of Life Sciences, Beijing University of Chinese Medicine, Beijing, China;
          [4 ]Department of Medicine and Liver Center, University of California, San Francisco, CA;
          [5 ]School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey;
          [6 ]Hepatic Surgery Center, Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China;
          [7 ]Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China;
          [8 ]Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Military Medical University, Xi’an, China;
          [9 ]Institute of Pathology, University of Regensburg, Regensburg, Germany;
          [10 ]Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China;
          [11 ]Institute of Pathology, University Medicine Greifswald, Greifswald, Germany;
          [12 ]Department of Pathology, University of Pittsburgh School of Medicine, and Pittsburgh Liver Research Center, Pittsburgh, PA.
          Author notes
          ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Xin Chen, Ph.D., Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA, 94143, xin.chen@ 123456ucsf.edu , Tel: +1 415 502-6526 Or Satdarshan P. Monga, M.D., Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop St. S-422 BST, Pittsburgh, PA, 15261, smonga@ 123456pitt.edu , Tel: +1 412-648-9966 or Junyan Tao, Ph.D., Department of Pathology, University of Pittsburgh School of Medicine, 200 Lothrop St. S-422 BST, Pittsburgh, PA, 15261, jut24@ 123456pitt.edu , Tel: +1 4123837821
          Author information
          http://orcid.org/0000-0001-7971-8725
          http://orcid.org/0000-0002-9588-0164
          Article
          PMC7206928 PMC7206928 7206928 nihpa1581860
          10.1002/hep.30556
          7206928
          30737831
          8770c4c7-649c-4b64-90cb-907c0f40a296
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