title: Dysregulated YAP1/TAZ and TGF-β signaling mediate hepatocarcinogenesis in Mob1a/1b-deficient mice.
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.
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Miki
authors.initials: M
authors.lastname: Nishio
authors.affiliation: Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan;
authors.forename: Keishi
authors.initials: K
authors.lastname: Sugimachi
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Goto
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Jia
authors.initials: J
authors.lastname: Wang
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Takumi
authors.initials: T
authors.lastname: Morikawa
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Miyachi
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takano
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hikasa
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo, Tokyo 113-8654, Japan;
authors.forename: Tohru
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan;
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.affiliation: Research Center for Advanced Science and Technology, The University of Tokyo, Bunkyo, Tokyo 113-8654, Japan;
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.affiliation: Faculty of Medicine, Saga University, Saga, Saga 840-8502, Japan;
authors.forename: Shinichi
authors.initials: S
authors.lastname: Aishima
authors.affiliation: Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada N6A 3K7;
authors.forename: Andrew
authors.initials: A
authors.lastname: Leask
authors.affiliation: Akita University Graduate School of Medicine, Akita, Akita 010-8502, Japan;
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Medical School and Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan;
authors.forename: Toru
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Medical Research Institute, Tokyo Medical and Dental University, Bunkyo, Tokyo 113-0034, Japan;
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
authors.affiliation: Asahikawa Medical University, Asahikawa, Hokkaido 078-8510, Japan;
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishikawa
authors.affiliation: Aichi Cancer Center Research Institute, Nagoya, Aichi 464-8681, Japan;
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.affiliation: Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto, Kyoto 606-8501, Japan;
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: National Institute of Advanced Industrial Science and Technology, Chiyoda, Tokyo 100-8921, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shin-Ya
authors.affiliation: Kyushu University Beppu Hospital, Beppu, Oita 874-0838, Japan;
authors.forename: Koshi
authors.initials: K
authors.lastname: Mimori
authors.affiliation: Medical Institute of Bioregulation, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 819-0395, Japan; suzuki@bioreg.kyushu-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000473:pathology*; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000378:metabolism / Q000473:pathology*; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D016147:Genes, Tumor Suppressor; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; C432417:MOB1 protein, mouse; C529494:Mob1b protein, mouse; D010750:Phosphoproteins; D018125:Receptors, Transforming Growth Factor beta; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C406030:transforming growth factor beta2.3; D055513:Connective Tissue Growth Factor; D000217:Acyltransferases; C108675:TAFAZZIN protein, human; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Hippo pathway; MOB1; TGF-beta; ivermectin; liver cancer