title: Adhesion molecule-mediated hippo pathway modulates hemangioendothelioma cell behavior.
abstract: Hemangioendotheliomas are categorized as intermediate-grade vascular tumors that are commonly localized in the lungs and livers. The regulation of this tumor cell's proliferative and apoptotic mechanisms is ill defined. We recently documented an important role for Hippo pathway signaling via endothelial cell adhesion molecules in brain microvascular endothelial cell proliferation and apoptosis. We found that endothelial cells lacking cell adhesion molecules escaped from contact inhibition and exhibited abnormal proliferation and apoptosis. Here we report on the roles of adherens junction molecule modulation of survivin and the Hippo pathway in the proliferation and apoptosis of a murine hemangioendothelioma (EOMA) cell. We demonstrated reduced adherens junction molecule (CD31 and VE-cadherin) expression, increased survivin and Ajuba expression, and a reduction in Hippo pathway signaling resulting in increased proliferation and decreased activation of effector caspase 3 in postconfluent EOMA cell cultures. Furthermore, we confirmed that YM155, an antisurvivin drug that interferes with Sp1-survivin promoter interactions, and survivin small interference RNA (siRNA) transfection elicited induction of VE-cadherin, decreased Ajuba expression, increased Hippo pathway and caspase activation and apoptosis, and decreased cell proliferation. These findings support the importance of the Hippo pathway in hemangioendothelioma cell proliferation and survival and YM155 as a potential therapeutic agent in this category of vascular tumors.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsuneki
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA joseph.madri@yale.edu.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Madri
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D015820:Cadherins / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006390:Hemangioendothelioma / Q000378:metabolism / Q000473:pathology*; D000090683:Hippo Signaling Pathway; D007093:Imidazoles / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009285:Naphthoquinones / Q000494:pharmacology; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D053148:Caspase 3; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D060588:LIM Domain Proteins; D009285:Naphthoquinones; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000077022:Survivin; D000099152:Cadherin 5; C117749:Birc5 protein, mouse; C485607:ajuba protein, mouse; C523798:sepantronium