Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice
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 in...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 1; pp. E71 - E80 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.01.2016
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
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| Abstract | 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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| AbstractList | Patients with intrahepatic cholangiocellular carcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (cHC-CC) have worse prognoses than those with hepatocellular carcinoma and rarely show clinical responses to drugs. Our analyses of mice with liver-specific deletions of Mps One Binder Kinase Activator (MOB)1A/1B reveal that MOB1A/1B constitute the most important hub of Hippo signaling in mammalian liver. MOB1A/1B maintain hepatocyte stem/progenitor cell quiescence and are potent tumor suppressors, especially in cHC-CCs and ICCs. Because these functions depend on the Hippo target
Yap1
/
Taz
and the
Yap1/Taz
targets
Tgfb
s, our data point to a new therapeutic approach for liver cancer based on inhibition of MOB1-YAP1/TAZ and/or TGF-βs–SMADs signaling. Our demonstration that well-tolerated and already-approved antiparasitic drugs inhibit YAP1 signaling may point to a new route of treatment for these cancers that can be rapidly tested and implemented.
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 (
L
Mob1DKO) 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.
L
Mob1DKO 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. 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. 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.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. |
| Author | Nishio, Miki Nakano, Toru Aishima, Shinichi Sugimachi, Keishi Nishina, Hiroshi Goto, Hiroki Suzuki, Satoshi O. Wang, Jia Nakao, Kazuwa Hikasa, Hiroki Mimori, Koshi Kurihara, Hiroki Morikawa, Takumi Nishikawa, Yuji Shin-ya, Kazuo Sekido, Yoshitaka Itoh, Tohru Suzuki, Akira Leask, Andrew Miyachi, Yosuke Takano, Yusuke Sasaki, Takehiko |
| Author_xml | – sequence: 1 givenname: Miki surname: Nishio fullname: Nishio, Miki organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 2 givenname: Keishi surname: Sugimachi fullname: Sugimachi, Keishi organization: Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan – sequence: 3 givenname: Hiroki surname: Goto fullname: Goto, Hiroki organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 4 givenname: Jia surname: Wang fullname: Wang, Jia organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 5 givenname: Takumi surname: Morikawa fullname: Morikawa, Takumi organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 6 givenname: Yosuke surname: Miyachi fullname: Miyachi, Yosuke organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 7 givenname: Yusuke surname: Takano fullname: Takano, Yusuke organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 8 givenname: Hiroki surname: Hikasa fullname: Hikasa, Hiroki organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 9 givenname: Tohru surname: Itoh fullname: Itoh, Tohru organization: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo, Tokyo 113-8654, Japan – sequence: 10 givenname: Satoshi O. surname: Suzuki fullname: Suzuki, Satoshi O. organization: Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan – sequence: 11 givenname: Hiroki surname: Kurihara fullname: Kurihara, Hiroki organization: Research Center for Advanced Science and Technology, The University of Tokyo, Bunkyo, Tokyo 113-8654, Japan – sequence: 12 givenname: Shinichi surname: Aishima fullname: Aishima, Shinichi organization: Faculty of Medicine, Saga University, Saga, Saga 840-8502, Japan – sequence: 13 givenname: Andrew surname: Leask fullname: Leask, Andrew organization: Schulich School of Medicine and Dentistry,University of Western Ontario, London, ON, Canada N6A 3K7 – sequence: 14 givenname: Takehiko surname: Sasaki fullname: Sasaki, Takehiko organization: Akita University Graduate School of Medicine, Akita, Akita 010-8502, Japan – sequence: 15 givenname: Toru surname: Nakano fullname: Nakano, Toru organization: Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan – sequence: 16 givenname: Hiroshi surname: Nishina fullname: Nishina, Hiroshi organization: Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-0034, Japan – sequence: 17 givenname: Yuji surname: Nishikawa fullname: Nishikawa, Yuji organization: Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan – sequence: 18 givenname: Yoshitaka surname: Sekido fullname: Sekido, Yoshitaka organization: Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan – sequence: 19 givenname: Kazuwa surname: Nakao fullname: Nakao, Kazuwa organization: Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8501, Japan – sequence: 20 givenname: Kazuo surname: Shin-ya fullname: Shin-ya, Kazuo organization: National Institute of Advanced Industrial Science and Technology, Chiyoda, Tokyo 100-8921, Japan – sequence: 21 givenname: Koshi surname: Mimori fullname: Mimori, Koshi organization: Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan – sequence: 22 givenname: Akira surname: Suzuki fullname: Suzuki, Akira organization: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26699479$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1073/pnas.0911409107 10.1016/j.ajpath.2014.01.005 10.1002/hep.22218 10.1002/jcp.22219 10.1186/1471-213X-1-4 10.1172/JCI63735 10.1016/j.ajpath.2012.08.034 10.1038/nrc2853 10.1093/emboj/19.24.6778 10.1016/S0002-9440(10)62328-0 10.1126/scisignal.2004060 10.1111/cas.12227 10.1016/j.ccr.2009.09.026 10.1042/BJ20120150 10.1101/gad.11.10.1242 10.1016/j.cellsig.2011.04.007 10.1016/j.cell.2014.03.060 10.1371/journal.pntd.0001825 10.1002/cncr.24495 10.1002/gene.20039 10.1016/j.cell.2007.07.019 10.1016/S1074-7613(00)00044-3 10.1111/j.1432-0436.1990.tb00453.x 10.1152/ajprenal.00201.2007 10.1038/emboj.2008.63 10.1016/j.devcel.2010.06.015 10.1101/gad.1664408 10.1038/ncb1748 10.1101/gad.264234.115 10.1016/j.devcel.2010.11.012 10.1002/ijc.1440 10.1016/S0140-6736(03)14964-1 10.1002/art.30074 10.1038/nature10137 10.1016/j.celrep.2013.10.030 10.1016/j.cell.2011.02.031 10.1523/JNEUROSCI.23-06-02314.2003 10.1038/onc.2008.66 10.1016/j.cub.2007.10.039 10.1126/stke.3992007cm1 10.1242/dev.103168 10.1038/ncomms2791 10.1073/pnas.0911427107 10.1016/j.yrtph.2006.10.009 10.1016/j.cell.2006.01.005 10.1002/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V 10.1101/gad.1938710 10.1038/nrc1926 10.1007/s00441-007-0542-z 10.1016/j.cell.2006.05.030 10.1158/0008-5472.CAN-10-2164 10.1101/gad.1843810 10.1002/ijc.29073 10.15252/emmm.201404084 10.1136/gutjnl-2013-306373 10.1182/blood-2010-01-262675 10.1053/j.gastro.2013.02.009 10.1016/S0969-2126(03)00182-5 |
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| Keywords | TGF-beta liver cancer Hippo pathway MOB1 ivermectin |
| Language | English |
| License | Freely available online through the PNAS open access option. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 1K.M. and A.S. contributed equally to this work. Author contributions: M.N., K.M., and A.S. designed research; M.N., K.S., H.G., J.W., T.M., Y.M., Y.T., H.H., and K.S.-y. performed research; T.I., H.K., A.L., T.S., Y.N., and Y.S. contributed new reagents/analytic tools; M.N., K.S., T.I., S.O.S., S.A., T.N., H.N., Y.N., K.N., K.S.-y., K.M., and A.S. analyzed data; and A.S. wrote the paper. Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, and approved November 23, 2015 (received for review August 29, 2015) |
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| References | Germain L (e_1_3_3_37_2) 1988; 48 e_1_3_3_50_2 e_1_3_3_16_2 e_1_3_3_18_2 e_1_3_3_39_2 e_1_3_3_12_2 e_1_3_3_58_2 e_1_3_3_14_2 e_1_3_3_35_2 e_1_3_3_56_2 e_1_3_3_33_2 e_1_3_3_54_2 e_1_3_3_10_2 e_1_3_3_31_2 e_1_3_3_40_2 e_1_3_3_61_2 Kosaka Y (e_1_3_3_27_2) 2007; 31 National Academy of Sciences (e_1_3_3_59_2) 2011 e_1_3_3_5_2 e_1_3_3_7_2 e_1_3_3_9_2 e_1_3_3_29_2 e_1_3_3_23_2 e_1_3_3_48_2 e_1_3_3_25_2 e_1_3_3_46_2 e_1_3_3_1_2 e_1_3_3_44_2 e_1_3_3_21_2 e_1_3_3_42_2 e_1_3_3_63_2 e_1_3_3_51_2 Hashimoto H (e_1_3_3_52_2) 2009; 3 e_1_3_3_17_2 e_1_3_3_19_2 e_1_3_3_38_2 e_1_3_3_13_2 e_1_3_3_36_2 e_1_3_3_15_2 e_1_3_3_34_2 e_1_3_3_57_2 e_1_3_3_32_2 e_1_3_3_55_2 e_1_3_3_11_2 e_1_3_3_30_2 e_1_3_3_53_2 e_1_3_3_62_2 Anonymous (e_1_3_3_3_2) 1992; 70 e_1_3_3_60_2 Wang CC (e_1_3_3_45_2) 1982; 97 e_1_3_3_6_2 e_1_3_3_8_2 e_1_3_3_28_2 e_1_3_3_49_2 e_1_3_3_24_2 e_1_3_3_47_2 e_1_3_3_26_2 e_1_3_3_2_2 e_1_3_3_20_2 e_1_3_3_43_2 e_1_3_3_4_2 e_1_3_3_22_2 e_1_3_3_41_2 e_1_3_3_64_2 |
| References_xml | – ident: e_1_3_3_18_2 doi: 10.1073/pnas.0911409107 – ident: e_1_3_3_41_2 doi: 10.1016/j.ajpath.2014.01.005 – ident: e_1_3_3_39_2 doi: 10.1002/hep.22218 – ident: e_1_3_3_46_2 doi: 10.1002/jcp.22219 – ident: e_1_3_3_36_2 doi: 10.1186/1471-213X-1-4 – ident: e_1_3_3_28_2 doi: 10.1172/JCI63735 – volume-title: Guide for the Care and Use of Laboratory Animals year: 2011 ident: e_1_3_3_59_2 – ident: e_1_3_3_63_2 doi: 10.1016/j.ajpath.2012.08.034 – ident: e_1_3_3_30_2 doi: 10.1038/nrc2853 – ident: e_1_3_3_8_2 doi: 10.1093/emboj/19.24.6778 – ident: e_1_3_3_61_2 doi: 10.1016/S0002-9440(10)62328-0 – ident: e_1_3_3_11_2 doi: 10.1126/scisignal.2004060 – ident: e_1_3_3_6_2 doi: 10.1111/cas.12227 – ident: e_1_3_3_17_2 doi: 10.1016/j.ccr.2009.09.026 – ident: e_1_3_3_53_2 doi: 10.1042/BJ20120150 – ident: e_1_3_3_60_2 doi: 10.1101/gad.11.10.1242 – ident: e_1_3_3_5_2 doi: 10.1016/j.cellsig.2011.04.007 – ident: e_1_3_3_22_2 doi: 10.1016/j.cell.2014.03.060 – ident: e_1_3_3_44_2 doi: 10.1371/journal.pntd.0001825 – volume: 31 start-page: 333 year: 2007 ident: e_1_3_3_27_2 article-title: Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer publication-title: Int J Oncol – ident: e_1_3_3_29_2 doi: 10.1002/cncr.24495 – ident: e_1_3_3_54_2 doi: 10.1002/gene.20039 – ident: e_1_3_3_21_2 doi: 10.1016/j.cell.2007.07.019 – ident: e_1_3_3_57_2 doi: 10.1016/S1074-7613(00)00044-3 – ident: e_1_3_3_62_2 doi: 10.1111/j.1432-0436.1990.tb00453.x – ident: e_1_3_3_56_2 doi: 10.1152/ajprenal.00201.2007 – ident: e_1_3_3_16_2 doi: 10.1038/emboj.2008.63 – ident: e_1_3_3_23_2 doi: 10.1016/j.devcel.2010.06.015 – ident: e_1_3_3_9_2 doi: 10.1101/gad.1664408 – ident: e_1_3_3_33_2 doi: 10.1038/ncb1748 – ident: e_1_3_3_48_2 doi: 10.1101/gad.264234.115 – ident: e_1_3_3_34_2 doi: 10.1016/j.devcel.2010.11.012 – ident: e_1_3_3_2_2 doi: 10.1002/ijc.1440 – ident: e_1_3_3_1_2 doi: 10.1016/S0140-6736(03)14964-1 – volume: 70 start-page: 173 year: 1992 ident: e_1_3_3_3_2 article-title: Prevention and control of neurofibromatosis: Memorandum from a joint WHO/NNFF meeting publication-title: Bull World Health Organ – ident: e_1_3_3_58_2 doi: 10.1002/art.30074 – ident: e_1_3_3_7_2 doi: 10.1038/nature10137 – ident: e_1_3_3_10_2 doi: 10.1016/j.celrep.2013.10.030 – ident: e_1_3_3_24_2 doi: 10.1016/j.cell.2011.02.031 – ident: e_1_3_3_55_2 doi: 10.1523/JNEUROSCI.23-06-02314.2003 – ident: e_1_3_3_40_2 doi: 10.1038/onc.2008.66 – ident: e_1_3_3_20_2 doi: 10.1016/j.cub.2007.10.039 – volume: 97 start-page: 373 year: 1982 ident: e_1_3_3_45_2 article-title: Actions of avermectin B1a on GABA nerves publication-title: Prog Clin Biol Res – ident: e_1_3_3_32_2 doi: 10.1126/stke.3992007cm1 – volume: 48 start-page: 4909 year: 1988 ident: e_1_3_3_37_2 article-title: Biliary epithelial and hepatocytic cell lineage relationships in embryonic rat liver as determined by the differential expression of cytokeratins, alpha-fetoprotein, albumin, and cell surface-exposed components publication-title: Cancer Res – ident: e_1_3_3_42_2 doi: 10.1242/dev.103168 – ident: e_1_3_3_26_2 doi: 10.1038/ncomms2791 – ident: e_1_3_3_15_2 doi: 10.1073/pnas.0911427107 – ident: e_1_3_3_49_2 doi: 10.1016/j.yrtph.2006.10.009 – ident: e_1_3_3_4_2 doi: 10.1016/j.cell.2006.01.005 – ident: e_1_3_3_35_2 doi: 10.1002/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V – ident: e_1_3_3_14_2 doi: 10.1101/gad.1938710 – volume: 3 start-page: 243 year: 2009 ident: e_1_3_3_52_2 article-title: Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines publication-title: Drug Discov Ther – ident: e_1_3_3_31_2 doi: 10.1038/nrc1926 – ident: e_1_3_3_38_2 doi: 10.1007/s00441-007-0542-z – ident: e_1_3_3_19_2 doi: 10.1016/j.cell.2006.05.030 – ident: e_1_3_3_64_2 doi: 10.1158/0008-5472.CAN-10-2164 – ident: e_1_3_3_13_2 doi: 10.1101/gad.1843810 – ident: e_1_3_3_43_2 doi: 10.1002/ijc.29073 – ident: e_1_3_3_51_2 doi: 10.15252/emmm.201404084 – ident: e_1_3_3_47_2 doi: 10.1136/gutjnl-2013-306373 – ident: e_1_3_3_50_2 doi: 10.1182/blood-2010-01-262675 – ident: e_1_3_3_12_2 doi: 10.1053/j.gastro.2013.02.009 – ident: e_1_3_3_25_2 doi: 10.1016/S0969-2126(03)00182-5 |
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| Snippet | 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... Patients with intrahepatic cholangiocellular carcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (cHC-CC) have worse prognoses than those with... |
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| SubjectTerms | Adaptor Proteins, Signal Transducing - metabolism Animals Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Biological Sciences Carcinogenesis - metabolism Cell Line, Tumor Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Connective Tissue Growth Factor - metabolism Epithelial-Mesenchymal Transition Genes, Tumor Suppressor Humans Hyperplasia - genetics Hyperplasia - pathology Intracellular Signaling Peptides and Proteins Liver - pathology Liver Neoplasms - metabolism Liver Neoplasms - pathology Mice Mice, Knockout Mice, Nude Phosphoproteins - genetics Phosphoproteins - metabolism PNAS Plus Protein Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Receptor, Transforming Growth Factor-beta Type II Receptors, Transforming Growth Factor beta - metabolism Signal Transduction Transcription Factors - metabolism Transforming Growth Factor beta - metabolism Xenograft Model Antitumor Assays |
| Title | Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice |
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