siRNA inhibition of aspartyl-asparaginyl β-hydroxylase expression impairs cell motility, Notch signaling, and fetal growth

Gündoğan, Füsun; Bedoya, Armando; Gilligan, Jeffrey; Lau, Emily; Mark, Princess; Paepe, Monique E. De

doi:10.1016/j.prp.2011.06.001

Cited by 28 publications

(30 citation statements)

References 31 publications

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“…Furthermore, as demonstrated in the present work, GBM cells transduced with Lenti-sh-ASPH resulting in sustained inhibition of ASPH expression, exhibited reduced viability and directional motility. Correspondingly, si-RNA [5, 6, 34] or antisense oligonucleotides [12, 35] targeting ASPH and not Humbug, inhibit cell motility. Although catalytic activity was not specifically demonstrated to be inhibited by the MO-Is in the GBM cells, the most important consequence of inhibiting hydroxylase activity, i.e.…”

Section: Discussionmentioning

confidence: 99%

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Sturla

Tong

Hebda

et al. 2016

Heliyon

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BackgroundDespite therapeutic advances, survival with glioblastoma multiforme (GBM) remains below 15 months from diagnosis due to GBM’s highly infiltrative nature which precludes complete surgical resection. Patient outcomes could potentially be improved by targeting genes and pathways that drive neoplastic cell motility and invasiveness, including hypoxia-inducible factor-1 (HIF-1α), NOTCH, and aspartate-β-hydroxylase (ASPH).MethodsHuman astrocytoma biopsy specimens (n = 37), WHO Grades II–IV, were analyzed for levels and distributions of ASPH and HIF-1α immunoreactivity by immunohistochemical staining, and ASPH, Notch, JAG, HES1, HEY1 and HIF1α mRNA expression by quantigene multiplex analysis. The effects of small molecule inhibitors on ASPH’s catalytic activity, cell viability and directional motility were examined in vitro in established GBM cell lines and primary tumor cells from an invasive mouse model of GBM.ResultsThe highest grade astrocytoma, i.e. GBM was associated with the highest levels of ASPH and HIF1α, and both proteins were more abundantly distributed in hypoxic compared with normoxic regions of tumor. Furthermore, mining of the TCGA database revealed higher levels of ASPH expression in the mesenchymal subtype of GBM, which is associated with more aggressive and invasive behavior. In contrast, lower grade astrocytomas had low expression levels of ASPH and HIF1α. In vitro experiments demonstrated that small molecule inhibitors targeting ASPH’s catalytic activity significantly reduced GBM viability and directional motility. Similar effects occurred in GBM cells that were transduced with a lentiviral sh-ASPH construct.ConclusionThis study demonstrates that increased ASPH expression could serve as a prognostic biomarker of gliomas and may assist in assigning tumor grade when biopsy specimens are scant. In addition, the findings suggest that GBM treatment strategies could be made more effective by including small molecule inhibitors of ASPH.

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Section: Discussionmentioning

confidence: 99%

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Sturla

Tong

Hebda

et al. 2016

Heliyon

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“…Consequently, gestational ethanol exposure impaired transformation of maternal decidual arteries such that the degree of impairment correlated with timing and duration of the insult, and severity of IUGR. The paradoxical response of glycogen cells may have been due to ethanol-inhibition of trophoblast cell motility and invasion [4,5,7]. Impaired motility of glycogen cells into the mesometrial triangle could account for their observed accumulation in the junctional zone.…”

Section: Discussionmentioning

confidence: 99%

“…Histological sections of placenta with underlying mesometrial triangle (5 µm thick) were immunostained with monoclonal antibody to Cytokeratin (CK) to detect invasive trophoblastic cells at the implantation site as previously described [5,23]. Briefly, deparaffinized and rehydrated tissue slides were incubated in preheated EnVision TM FLEX Target Retrieval Solution (high pH=9.0) for 20 minutes at 95-100°C.…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…CK-positive invasive trophoblastic cells within the mesometrial triangle were quantified using unbiased stereology [5]. Numerical density calculation was performed with the aid of an Olympus BX60 light microscope (Olympus America Inc., Center Valley, PA) with attached MS-2000 XYZ Inverted Stage (Applied Scientific Instrumentation, Eugene, OR), and Stereologer software (Stereology Resource Center, Inc., Chester, MD).…”

Section: Stereologymentioning

confidence: 99%

“…Previous studies focused on the adverse effects of ethanol on insulin/IGF signaling in relation to trophoblast cell motility and invasiveness, and linked these abnormalities to impairments in placentation, intrauterine growth restriction, and early pregnancy loss [4]. In addition, the adverse effects of ethanol were found to be mediated by inhibition of Aspartyl-Asparaginylβ-Hydroxylase (AAH) [5]. AAH is aninsulin/IGF-responsive gene, whose hydroxylase activity regulates cell motility and invasion [6,7].…”

Section: Introductionmentioning

confidence: 99%

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A Potential Administration-time Dependent Effect of Bevacizumab in Improving Overall Survival and Increasing Metastasis in Metastatic Colorectal Cancer

Zhang¹,

He²,

Zhou³

et al. 2013

Chemotherapy

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Background: One of the major adverse effects of maternal ethanol consumption is intrauterine growth restriction (IUGR). Previous studies demonstrated that ethanol-induced IUGR is mediated by impaired placentation. Chronic gestational ethanol exposure reduces trophoblastic cell motility and invasiveness through inhibition of insulin/IGF signaling leading to impaired vascular transformation at the implantation site. Furthermore, ethanol reduces the number of secondary giant cells that mediate vascular invasion in rat placenta. However, the degree to which ethanol inhibits progenitor cell survival and differentiation is not known.

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A novel ASPH variant extends the phenotype of Shawaf‐Traboulsi syndrome

Barriga

Caballero

Trubnykova

et al. 2018

American J of Med Genetics Pt A

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Shawaf-Traboulsi syndrome (or Traboulsi syndrome; MIM 601552) is an infrequently reported entity characterized by a typical face (long face, large nose, convex nasal ridge, underdeveloped malae, crowded teeth, retrognathia), skeletal signs (long and slender fingers, sometimes pectus deformation and hypermobile joints), and ectopia lentis with conjunctival blebs, shallow anterior chamber and iridocorneal adhesions. The entity is caused by homozygous variants in ASPH. Here, we report on a boy with the clinical diagnosis of Shawaf-Traboulsi syndrome, in whom exome sequencing allowed identification of a novel variant in ASPH. We compare the findings in the present patient to those of earlier reported patients; furthermore add new signs for this entity.

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siRNA inhibition of aspartyl-asparaginyl β-hydroxylase expression impairs cell motility, Notch signaling, and fetal growth

Cited by 28 publications

References 31 publications

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

Aspartate-β-hydroxylase (ASPH): A potential therapeutic target in human malignant gliomas

A Potential Administration-time Dependent Effect of Bevacizumab in Improving Overall Survival and Increasing Metastasis in Metastatic Colorectal Cancer

A novel ASPH variant extends the phenotype of Shawaf‐Traboulsi syndrome

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