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.

Modulation of Sox10, HIF-1α, Survivin, and YAP by Minocycline in the Treatment of Neurodevelopmental Handicaps following Hypoxic Insult

“…Our findings of increased minocycline-mediated Sox10 23 and HIF-1a, 14,18,19 as well as YAP and survivin induction 62,63 are consistent with an emerging dynamic interaction among these important modulators of the hypoxic response. 34 Specifically, minocycline-induced Sox10 and HIF-1a (and their downstream signaling pathways 14,18,19 ) and myelination-associated genes, 23 also up-regulate YAP and survivin, both of which also positively influence each other's expression, 63 increasing proliferation and decreasing apoptosis.…”

“…34 Specifically, minocycline-induced Sox10 and HIF-1a (and their downstream signaling pathways 14,18,19 ) and myelination-associated genes, 23 also up-regulate YAP and survivin, both of which also positively influence each other's expression, 63 increasing proliferation and decreasing apoptosis. 63 Furthermore, investigators have recently found that hypoxia-induced SIAH2, an E3 ligase, destabilizes LATS2 Q23 , reducing Hippo pathway activation, increasing YAP signaling, and affecting proliferation and apoptosis. 34 They also determined that YAP complexes with HIF-1a in the nucleus, stabilizing HIF-mediated signaling, affecting survival, proliferation, and apoptosis.…”

A hydrogel-endothelial cell implant mimics infantile hemangioma: modulation by survivin and the Hippo pathway

“…In addition, in light of our recent findings demonstrating a role for Survivin and Hippo pathway components as modulators of endothelial and hemangioendothelioma proliferation and apoptosis in vitro 9, 14 , we embarked upon an assessment of components of these pathways in our murine model and in patient samples of infantile hemangioma. Interestingly, we found early (two week) implants and proliferating infantile hemangiomas exhibited more robust Survivin, YAP and Ajuba staining than late (four week) implants and involutional infantile hemangiomas.…”

“…WT-BEC was cultured on 1.5% gelatin (Cat No. G8-500, Thermo Fisher Scientific Inc., Waltham, MA, USA) coated plates in brain endothelial cell media [Dulbecco’s Modified Eagle’s Medium (DMEM) with High Glucose (Life Technologies, Grand Island, NY, USA) containing 10% FBS, 2 mM L-glutamine, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, 10 mM HEPES (pH 7.4), 10 −5 M β-mercaptoethanol, 100 U/ml penicillin, and 100 μg/ml streptomycin (Life Technologies)] in 8% CO 2 at 37°C 9, 16 . Cells were used passage 22 and cultured under normoxic (20% O 2 ) condition.…”

“…In addition, implantation of cells in three-dimensional scaffolds has been used to enhance survivability 6 , investigate basic physiological and pathophysiological processes including angiogenesis 7, 8 , cell migration and invasion 9 , differentiation 10 and neoplasia 11 . Using both biological (collagen and other ECM components) and biocompatible (hydrogels) scaffolds we have demonstrated their efficacy in combination with selected cell types as protein delivery vehicles 5 , several angiogenesis studies and neural progenitor studies 10, 12, 13 .…”