Interacting network of Hippo, Wnt/β-catenin and Notch signaling represses liver tumor formation

Wantae Kim, Sanjoy Kumar Khan, Yingzi Yang

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

Acquiring a selective growth advantage by breaking theproliferation barrier established by gatekeeper genes is acentrally important event in tumor formation. Removal of themammalian Hippo kinase Mst1 and Mst2 in hepatocytes leadsto rapid hepatocellular carcinoma (HCC) formation, indicatingthat the Hippo signaling pathway is a critical gatekeeper thatrestrains abnormal growth in hepatocytes. By rigorous geneticapproaches, we identified an interacting network of the Hippo,Wnt/β-catenin and Notch signaling pathways that control organsize and HCC development. We found that in hepatocytes, theloss of Mst1/2 leads to the activation of Notch signaling, whichforms a positive feedback loop with Yap/Taz (transcription factorscontrolled by Mst1/2). This positive feedback loop results insevere liver enlargement and rapid HCC formation. Blockingthe Yap/Taz-Notch positive feedback loop by Notch inhibitionin vivo significantly reduced the Yap/Taz activities, hepatocyteproliferation and tumor formation. Furthermore, we uncovereda surprising inhibitory role of Wnt/β-catenin signaling toYap/Taz activities, which are important in tumor initiation.Genetic removal of β-catenin in the liver of the Mst1/2 mutantssignificantly accelerates tumoriogenesis. Therefore, Wnt/β-cateninsignaling, known for its oncogenic property, exerts anunexpected function in restricting Yap/Taz and Notch activitiesin HCC initiation. The molecular interplay between the threesignaling pathways identified in our study provides newinsights in developing novel therapeutic strategies to treat livertumors.

Original languageEnglish
Pages (from-to)1-2
Number of pages2
JournalBMB Reports
Volume50
Issue number1
DOIs
StatePublished - 2017

Keywords

  • HCC
  • Hippo
  • Notch pathways
  • Wnt/β-catenin
  • Yap/Taz

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