期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 1, 页码 E71-E80出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1517188113
关键词
MOB1; Hippo pathway; liver cancer; ivermectin; TGF-beta
资金
- Ministry of Education, Culture, Sports and Technology of Japan
- P-DIRECT
- Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University
- Uehara Memorial Foundation
- Takeda Medical Foundation
- Mitsui Life Social Welfare Foundation
- Grants-in-Aid for Scientific Research [15K15107, 26293012, 24390092] Funding Source: KAKEN
Mps One Binder Kinase Activator (MOB) 1A/1B are core components of the Hippo pathway that coactivate large tumor suppressor homolog (LATS) kinases. Mob1a/1b double deficiency in mouse liver (LMob1DKO) results in hyperplasia of oval cells and immature cholangiocytes accompanied by inflammatory cell infiltration and fibrosis. More than half of mutant mice die within 3 wk of birth. All survivors eventually develop liver cancers, particularly combined hepatocellular and cholangiocarcinomas (cHC-CCs) and intrahepatic cholangiocellular carcinomas (ICCs), and die by age 60 wk. Because this phenotype is the most severe among mutant mice lacking a Hippo signaling component, MOB1A/1B constitute the critical hub of Hippo signaling in mammalian liver. LMob1DKO liver cells show hyperproliferation, increased cell saturation density, hepatocyte dedifferentiation, enhanced epithelial-mesenchymal transition and cell migration, and elevated transforming growth factor beta(TGF-beta)2/3 production. These changes are strongly dependent on Yes-Associated Protein-1 (Yap1) and partially dependent on PDZ-binding motif (Taz) and Tgfbr2, but independent of connective tissue growth factor (Ctgf). In human liver cancers, YAP1 activation is frequent in cHC-CCs and ICCs and correlates with SMAD family member 2 activation. Drug screening revealed that antiparasitic macrocyclic lactones inhibit YAP1 activation in vitro and in vivo. Targeting YAP1/TAZ with these drugs in combination with inhibition of the TGF-beta pathway may be effective treatment for cHC-CCs and ICCs.
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