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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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Abstract. The expression levels of connexin (Cx) proteins, which are gap junction (GJ) components, are often decreased in many cancers, and restoring their levels has been shown to have antitumor effects. Previously, dysfunctional gap junctional intercellular communication (GJIC) has been observed in several malignant mesotheliomas (MMs), and among the many Cx proteins, Cx43 is prominently expressed in nontumorigenic mesothelial tissues. Therefore, we investigated whether Cx43 upregulation has an antitumor effect on an MM cell line (H28 cell), especially with regard to drug resistance. After treatment with the chemotherapeutic agent cisplatin (CDDP), MM cell viability significantly decreased, and apoptosis induction was observed in Cx43-transfected clones. A specific GJIC inhibitor could not abrogate this effect. On the other hand, the Src protein is known to phosphorylate Cx43, which results in GJIC inhibition. This suggests that Src activity might also be regulated by the hyperexpression of Cx43. In fact, the Src protein level was decreased in Cx43-transfected clones. Moreover, Src inhibition reinforced CDDP cytotoxicity in parental H28 cells. These data suggest that Cx43 could improve the resistance to CDDP in a GJIC-independent manner, which may be partly mediated by the suppression of Src activity.