title: Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis.
abstract: Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/β-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/β-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/β-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations.
authors.forename: Wantae
authors.initials: W
authors.lastname: Kim
authors.forename: Sanjoy Kumar
authors.initials: SK
authors.lastname: Khan
authors.forename: Jelena
authors.initials: J
authors.lastname: Gvozdenovic-Jeremic
authors.forename: Youngeun
authors.initials: Y
authors.lastname: Kim
authors.forename: Jason
authors.initials: J
authors.lastname: Dahlman
authors.forename: Hanjun
authors.initials: H
authors.lastname: Kim
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Tohru
authors.initials: T
authors.lastname: Ishitani
authors.forename: Eek-Hoon
authors.initials: EH
authors.lastname: Jho
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Yang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D000090742:Serine-Threonine Kinase 3; D060449:Wnt Signaling Pathway; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D000099317:Hippo Kinases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D017228:Hepatocyte Growth Factor; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D000090742:Serine-Threonine Kinase 3; D000091102:YAP-Signaling Proteins; D051176:beta Catenin; C494087:Stat3 protein, mouse; C486223:Yap1 protein, mouse; C082332:macrophage stimulating protein; C490818:Stk3 protein, mouse; D000099317:Hippo Kinases