TY - JOUR
T1 - Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice
AU - Nishio, Miki
AU - Sugimachi, Keishi
AU - Goto, Hiroki
AU - Wang, Jia
AU - Morikawa, Takumi
AU - Miyachi, Yosuke
AU - Takano, Yusuke
AU - Hikasa, Hiroki
AU - Itoh, Tohru
AU - Suzuki, Satoshi O.
AU - Kurihara, Hiroki
AU - Aishima, Shinichi
AU - Leask, Andrew
AU - Sasaki, Takehiko
AU - Nakano, Toru
AU - Nishina, Hiroshi
AU - Nishikawa, Yuji
AU - Sekido, Yoshitaka
AU - Nakao, Kazuwa
AU - Shin-Ya, Kazuo
AU - Mimori, Koshi
AU - Suzuki, Akira
N1 - Funding Information:
We thank A. Miyajima and K. Miyazono (both of Tokyo University); K. Enomoto (Akita University); M. Fukumoto (Tohoku University); M. Kasagi, A. Fujimoto, A. Suzuki, and M. Suzuki (all of Kyushu University); and S. Maegawa, J. Utsumi, F. Ishikawa, M. Seiki, and T. Noda (all of P-DIRECT) for expert technical assistance and helpful discussions. We thank J. Roes (University College London) and P. Chambon (Université de Strasbourg) for Tgfbr2flox and AlbCreER Tg mice, respectively. We thank V. M. Factor (National Institutes of Health) for A6 antibody. This work was supported by grants from the Ministry of Education, Culture, Sports and Technology of Japan (to A.S., M.N., and J.W.); P-DIRECT (to A.S.); the Cooperative Research Project Program of the Medical Institute of Bioregulation, Kyushu University; the Uehara Memorial Foundation (to A.S.); the Takeda Medical Foundation (to A.S.); and the Mitsui Life Social Welfare Foundation (to K.S.).
PY - 2016/1/5
Y1 - 2016/1/5
N2 - 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-β)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-β pathway may be effective treatment for cHC-CCs and ICCs.
AB - 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-β)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-β pathway may be effective treatment for cHC-CCs and ICCs.
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U2 - 10.1073/pnas.1517188113
DO - 10.1073/pnas.1517188113
M3 - Article
C2 - 26699479
AN - SCOPUS:84953230626
VL - 113
SP - E71-E80
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 1
ER -