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1.
J Biol Regul Homeost Agents ; 34(1): 49-56, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32138500

RESUMO

Dysregulation of lncRNA cancer susceptibility candidate 2 (CASC2) is involved in the pathogenesis of multiple malignancies. However, the underlying mechanisms by which lncRNA CASC2 regulates the proliferation of hemangiomas (HAs) remain undocumented. Herein, the expression levels of lncRNA CASC2 and VEGF in proliferating or involuting phase HAs were assessed by qRT-PCR analysis, and the effects of lncRNA CASC2 on HAs cell growth were evaluated by MTT, colony formation assays and Western blot analysis. lncRNA CASC2 specific binding with miR-18a-5p was confirmed by luciferase report assay. Consequently, we found that the expression of lncRNA CASC2 was reduced in proliferating phase HAs as compared with the involuting phase HAs or normal tissues, and possessed a negative correlation with VEGF expression in proliferating phase HAs. Restored expression of lncRNA CASC2 repressed cell viability and colony formation and downregulated VEGF expression, while silencing lncRNA CASC2 showed the opposite effects. Moreover, lncRNA CASC2 was confirmed to bind with miR-18a-5p, which could reverse lncRNA CASC2-induced anti-proliferative effects by targeting FBXL3 in HAs cells. Altogether, our findings demonstrated that lncRNA CASC2 suppressed the growth of HAs cells by regulating miR-18a-5p/FBXL3 axis.


Assuntos
Proteínas F-Box/genética , Hemangioma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Proteínas Supressoras de Tumor/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Hemangioma/patologia , Humanos , Fator A de Crescimento do Endotélio Vascular
2.
Virchows Arch ; 476(1): 17-28, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31463731

RESUMO

The classification of vascular neoplasms continues to evolve as we accumulate more genetic and clinical data, particularly for rare tumor types. Because of tumor rarity, changes to classification schema, overlapping histologic features, and in some cases, lack of morphologic evidence of vasoformation, vascular neoplasms present a diagnostic challenge. Here, we discuss recent developments in our understanding of vascular tumors, with a detailed discussion of epithelioid hemangioma, tufted angioma, kaposiform hemangioendothelioma, composite hemangioendothelioma, pseudomyogenic hemangioendothelioma, epithelioid hemangioendothelioma, and angiosarcoma.


Assuntos
Neoplasias Vasculares/patologia , Proteínas de Ligação ao Cálcio/genética , Hemangioendotelioma/genética , Hemangioendotelioma/patologia , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Hemangioma/genética , Hemangioma/patologia , Hemangiossarcoma/genética , Hemangiossarcoma/patologia , Humanos , Síndrome de Kasabach-Merritt/genética , Síndrome de Kasabach-Merritt/patologia , Proteínas Proto-Oncogênicas c-myc/análise , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Transativadores/genética , Neoplasias Vasculares/genética
3.
Tech Vasc Interv Radiol ; 22(4): 100634, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31864529

RESUMO

Klippel-Trenaunay syndrome or KTS is a complex vascular syndrome associated with overgrowth occurring as a result of somatic mutations in the PIK3CA gene. Patients are diagnosed on the basis of physical findings, sometimes with supportive imaging, of commonly a segmental anomaly with a cutaneous port-wine stain, lymphatic and venous malformations and overgrowth. The severity of the component vascular malformations and the degree of overgrowth varies from patient to patient which demands care given by a multi-professional team with regular follow-up in a specialist clinic. Some patients may present with acute life-threatening problems, often as a result of veno-thromboembolic events (VTEs) especially following surgical and invasive radiological procedures. Awareness of such problems is vital and prophylactic measures to reduce such risks are paramount. The interventional radiologist is vital to the care team as he/she can undertake procedures including endovascular closure of significant venous anomalies which predispose to such VTEs. Although these procedures can be lengthy and complex, they can now provide a minimally invasive means to reduce the risk from life-threatening and sometimes fatal VTEs. The results however from such interventions will require long-term studies which to date are unavailable.


Assuntos
Malformações Arteriovenosas/terapia , Procedimentos Endovasculares , Síndrome de Klippel-Trenaunay-Weber/terapia , Tromboembolia Venosa/prevenção & controle , Malformações Arteriovenosas/diagnóstico , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/mortalidade , Classe I de Fosfatidilinositol 3-Quinases/genética , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Predisposição Genética para Doença , Hemangioma/diagnóstico , Hemangioma/genética , Hemangioma/terapia , Humanos , Síndrome de Klippel-Trenaunay-Weber/diagnóstico , Síndrome de Klippel-Trenaunay-Weber/genética , Síndrome de Klippel-Trenaunay-Weber/mortalidade , Mutação , Fenótipo , Radiografia Intervencionista , Fatores de Risco , Resultado do Tratamento , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/genética , Tromboembolia Venosa/mortalidade
4.
BMC Med Genet ; 20(1): 176, 2019 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-31711431

RESUMO

BACKGROUND: Pulmonary hypertension (PH) remains one of the rarest and deadliest diseases. Pulmonary Capillary Hemangiomatosis (PCH) is one of the sub-classes of PH. It was identified using histological and molecular tools and is characterized by the proliferation of capillaries into the alveolar septae. Mutations in the gene encoding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) have recently been linked to this particular subgroup of PH. METHODS: In our effort to unveil the genetic basis of idiopathic and familial cases of PH in Lebanon, we have used whole exome sequencing to document known and/or novel mutations in genes that could explain the underlying phenotype. RESULTS: We showed bi-allelic mutations in EIF2AK4 in two non-consanguineous families: a novel non-sense mutation c.1672C > T (p.Q558*) and a previously documented deletion c.560_564drlAAGAA (p.K187Rfs9*). Our histological analysis coupled with the CT-scan results showed that the two patients with the p.Q558* mutation have PH. In contrast, only one of the individuals harboring the p.K187Rfs9* variant has a documented PCH while his older brother remains asymtomatic. Differential analysis of the variants in the genes of the neighboring network of EIF2AK4 between the two siblings identified a couple of interesting missense mutations that could account for this discrepancy. CONCLUSION: These findings represent a novel documentation of the involvement of EIF2AK4 in the different aspects of pulmonary hypertension. The absence of a molecular mechanism that relates the abrogated function of the protein to the phenotype is still a major hurdle in our understanding of the disease.


Assuntos
Capilares/patologia , Hemangioma/genética , Hipertensão Pulmonar/genética , Pulmão/irrigação sanguínea , Mutação , Proteínas Serina-Treonina Quinases/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
5.
Life Sci ; 239: 116946, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31610202

RESUMO

AIMS: Infantile hemangioma (IH) is the most common vascular neoplasm in infant and young children. Long non-coding RNAs (lncRNAs) are known to be associated with IH. This study aims to investigate the role and underlying mechanism of lncRNA-MALAT1 in IH. MAIN METHODS: qRT-PCR was used to quantify the expressions of MALAT1, miR-424, and MEKK3 in IH tissues. The cell proliferation, apoptosis, migration, invasion, and tube formation ability were assessed by MTT assay, colony formation assay, flow cytometric analysis, transwell assay and tube formation assay, respectively. The interaction among MALAT1, miR-424 and MEKK3 was evaluated by luciferase reporter assay. Immunohistochemistry (IHC) and Western blotting were utilized to evaluate the expression levels of MEKK3, Ki-67 and NF-κB pathway-related proteins both in vitro and in vivo. KEY FINDINGS: In IH tissues, MALAT1 and MEKK3 were overexpressed while miR-424 was down-regulated. Silencing MALAT1 or overexpression of miR-424 significantly inhibited the IH cell proliferation, migration and tube formation, but promoted the cell apoptosis. Knockdown of MALAT1 suppressed the expression of MEKK3 and inactivated the IKK/NF-κB pathway by sponging miR-424. Overexpression of MEKK3 in HemEcs reversed the impact of knockdown of MALAT1 and overexpression of miR-424 on the cell proliferation, apoptosis, migration, invasion and tube formation rate. The tumor xenografts experiments demonstrated that silencing MALAT1 significantly inhibited the tumor growth in vivo and Ki-67 in the tumor tissues was also significantly suppressed. SIGNIFICANCE: MALAT1 promoted the IH progression through inhibiting miR-424 to activate MEKK3-mediated IKK/NF-κB pathway, suggesting that MALAT1, miR-424 and MEKK3 could be used as potential targets to improve IH treatment efficiency.


Assuntos
Hemangioma/metabolismo , MAP Quinase Quinase Quinase 3/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Hemangioma/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , NF-kappa B/metabolismo , Invasividade Neoplásica , RNA Longo não Codificante/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Fam Cancer ; 18(4): 445-449, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31240424

RESUMO

A 51-year old presented with a 6-month history of increasing pelvic/lower back pain with nocturnal waking and episodes of anorexia and vomiting. Examination revealed right torticollis and Horner's syndrome, and a large abdominal mass arising from the pelvis. Magnetic resonance and positron emission tomography imaging revealed (A) a 14 cm heterogeneous enhancing mass, abutting the left kidney with standardised uptake value max = 2.9, (B) a large heterogeneous enhancing pelvic mass (C) mesenteric adenopathy standardised uptake value max = 10.3 and (D) 6 cm right lung apex mass standardised uptake value max = 4.3. Computerised tomography-guided biopsy of lesion A was reported as neurofibroma with occasional atypia, lesion B a benign uterine leiomyoma and lesion C follicular lymphoma world health organisation Grade 2. Although she had been given the diagnosis of Neurofibromatosis Type-1 (NF1) 25-years previously following removal of an intradural extramedullary schwannoma she had no cutaneous stigmata of NF1. Genetic analysis of blood lymphocyte DNA identified a pathogenic variant in SMARCB1 confirming a diagnosis of schwannomatosis. Following 6-months chemotherapy for lymphoma, surgery was performed to remove lesion A. Histology revealed a malignant peripheral nerve sheath tumour with areas of low and high-grade change. An incidental, well-differentiated small bowel neuroendocrine carcinoma was also excised. Close surveillance continues with no recurrence after 6 years. This case study describes a novel finding of three separate synchronous primary malignancies in a patient with schwannomatosis and a proven SMARCB1 pathogenic variant.


Assuntos
Hemangioma/genética , Neoplasias Primárias Múltiplas/genética , Neurilemoma/genética , Neurofibromatoses/genética , Neurofibrossarcoma/genética , Proteína SMARCB1/genética , Neoplasias Cutâneas/genética , Feminino , Hemangioma/terapia , Síndrome de Horner/diagnóstico por imagem , Humanos , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/complicações , Neoplasias Primárias Múltiplas/patologia , Neoplasias Primárias Múltiplas/terapia , Neurilemoma/complicações , Neurilemoma/patologia , Neurilemoma/terapia , Neurofibromatoses/complicações , Neurofibromatoses/terapia , Neurofibrossarcoma/patologia , Neurofibrossarcoma/terapia , Neoplasias Retroperitoneais/genética , Neoplasias Retroperitoneais/terapia , Neoplasias Cutâneas/complicações , Neoplasias Cutâneas/terapia
7.
Toxicol In Vitro ; 60: 323-329, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31212022

RESUMO

Hemangioma (HA) are tumors formed by hyper-proliferation of vascular endothelial cells. As a potential endocrine disrupting chemical (EDC), benzyl butyl phthalate (BBP) can mimic estrogen to disturb the estrogenic signals. Our present study investigated the potential roles of phthalates on the progression of HA and found that 100 nM BBP can significantly trigger the migration and invasion of HA cells, which was evidenced by the results that BBP can induce the expression of matrix metalloproteinase (MMPs) and vimentin. Further, BBP can increase the expression of Zeb1, one powerful transcription factor for cell migration and invasion. Targeted inhibition of Zeb1 blocked BBP induced cell migration. Mechanistically, BBP can increase the mRNA stability of Zeb1 via suppression of miR-655. Further, BBP can enhance the protein stability of Zeb1 via upregulation of ataxia telangiectasia mutated (ATM). Collectively, our present study revealed that BBP can trigger the migration and invasion of HA cells via upregulation of Zeb1.


Assuntos
Disruptores Endócrinos/toxicidade , Hemangioma/genética , Ácidos Ftálicos/toxicidade , Plastificantes/toxicidade , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Hemangioma/patologia , Humanos , MicroRNAs/genética , Regulação para Cima/efeitos dos fármacos
8.
Int J Mol Sci ; 20(13)2019 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-31252633

RESUMO

We investigated protein profiles specific to vascular lesions mimicking Kaposi sarcoma (KS), based on stepwise morphogenesis progression of KS. We surveyed 26 tumor-associated proteins in 130 cases, comprising 39 benign vascular lesions (BG), 14 hemangioendotheliomas (HE), 37 KS, and 40 angiosarcomas (AS), by immunohistochemistry. The dominant proteins in KS were HHV8, lymphatic markers, Rb, phosphorylated Rb, VEGF, and galectin-3. Aberrant expression of p53, inactivation of cell cycle inhibitors, loss of beta-catenin, and increased VEGFR1 were more frequent in AS. HE had the lowest Ki-67 index, and the inactivation rates of cell cycle inhibitors in HE were between those of AS and BG/KS. Protein expression patterns in BG and KS were similar. Clustering analysis showed that the 130 cases were divided into three clusters: AS-rich, BG-rich, and KS-rich clusters. The AS-rich cluster was characterized by high caveolin-1 positivity, abnormal p53, high Ki-67 index, and inactivated p27. The KS-rich cluster shared the features of KS, and the BG-rich group had high positive expression rates of galectin-3 and low bcl2 expression. In conclusion, although the rate was different, AS and HE tended to have less cell cycle marker expression than KS, and features of BG and activated KS cell signaling were similar.


Assuntos
Biomarcadores Tumorais/sangue , Hemangioma/sangue , Sarcoma de Kaposi/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Diagnóstico Diferencial , Feminino , Galectina 3/sangue , Galectina 3/genética , Galectina 3/metabolismo , Regulação Neoplásica da Expressão Gênica , Hemangioma/genética , Hemangioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-2/sangue , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia
9.
Anticancer Res ; 39(5): 2351-2360, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092427

RESUMO

BACKGROUND/AIM: Hepatic hemangiomas (HH) can show an aggressive course with significant complications. Prognostic markers that identify an aggressive course are entirely absent. Since we have showed that Hedgehog signaling is overexpressed in aggressive hemangiomas of the skin. Here, we hypothesize that it is also altered in aggressive HH. MATERIALS AND METHODS: Immunohistological staining for GLUT1 and quantitative PCR was performed in seven specimens with aggressive HH. For comparison, we included specimens of kaposiform hemangioendothelioma (KHE), skin hemangioma and normal liver tissue. RESULTS: Overexpression of the Hedgehog signaling components SHH and GLI2 and its target gene FOXA2 in HH were similar to those found in aggressive skin hemangioma and KHE, their expression being significantly higher than in mild skin hemangioma. High expression levels of SHH and FOXA2 positively correlated with HH, but not with normal liver tissue. CONCLUSION: Hedgehog signaling is up-regulated in aggressive HH. This finding may lead to a biomarker allowing early intervention.


Assuntos
Proteínas Hedgehog/genética , Hemangioma/genética , Fator 3-beta Nuclear de Hepatócito/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Proteína Gli2 com Dedos de Zinco/genética , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Transportador de Glucose Tipo 1/genética , Hemangioendotelioma/genética , Hemangioendotelioma/patologia , Hemangioma/patologia , Humanos , Lactente , Recém-Nascido , Síndrome de Kasabach-Merritt/genética , Síndrome de Kasabach-Merritt/patologia , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/patologia , Transdução de Sinais/genética
10.
Life Sci ; 226: 33-46, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30898646

RESUMO

BACKGROUND: Human urothelial carcinoma associated 1 (UCA1) has been recognized as an oncogenic lncRNA in various cancers, except infantile hemangioma (IH). This study attempts to explore the functional role of lncRNA UCA1 in IH. METHODS: qRT-PCR was carried out to detect the expression of lncRNA UCA1 in human IH tissues. Two hemangioma cell lines (EOMA and HemECs) were transfected with shRNAs specific for lncRNA UCA1, or a plasmid for expression lncRNA UCA1. The expression of miR-200c in cell was suppressed or overexpressed by miRNA-mediated transfection. CCK-8 assay, flow cytometry, Transwell assay, and Western blot were performed to detect cell survival, migration and invasion. RESULTS: LncRNA UCA1 was up-regulated in proliferating-phase hemangioma samples, as compared to involuting-phase. Silence of lncRNA UCA1 significantly reduced EOMA cells viability, migration and invasion, and induced apoptosis. These observations were coupled with the down-regulations of CyclinD1, CDK6 and CDK4, the cleavage of caspase-3 and caspase-9, as well as the decreased expression levels of MMP-9 and Vimentin. miR-200c was highly expressed in lncRNA UCA1 silenced-cells. Besides, the anti-tumor effects of lncRNA UCA1 silence towards EOMA cells were reversed by miR-200c suppression. Same effects of lncRNA UCA1 and miR-200c on HemECs cells were observed. Furthermore, silence of lncRNA UCA1 repressed mTOR, AMPK and Wnt/ß-catenin signaling via a miR-200c-dependent fashion. CONCLUSION: This study evidences that silence of lncRNA UCA1 inhibits hemangioma cells growth, migration and invasion possibly via its regulation on miR-200c expression and the activation of mTOR, AMPK and Wnt/ß-catenin signaling pathways.


Assuntos
Hemangioma/genética , Hemangioma/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Adenilato Quinase/genética , Adenilato Quinase/metabolismo , Animais , Apoptose/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Feminino , Hemangioma/metabolismo , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , MicroRNAs/genética , Invasividade Neoplásica , RNA Longo não Codificante/genética , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Ativação Transcricional , Regulação para Cima , Via de Sinalização Wnt
11.
Life Sci ; 223: 22-28, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30851338

RESUMO

AIMS: Infantile hemangioma (IH) is one of the most common benign vascular tumors occurred in infants. Linc00152 is a kind of long non-coding RNAs (lncRNAs) and acts as a tumor oncogene. Recent study reported that Linc00152 is highly expressed in clinical IH tissues. However, the exact biological roles have not yet been investigated. The aim of the present study was to investigate the oncogenic roles of Linc00152 in IH and the underlying mechanism in vitro. MAIN METHODS: The expressions of Linc00152 in IH tissues and hemangioma-derived endothelial cells (HemECs) were determined using quantitative real time-PCR (qRT-PCR) analysis. The expressions of Akt/mTOR and Notch1 pathways related proteins were detected using western blot analysis. Cell proliferation was assessed by detecting Ki67 expression and CCK-8 assay. Cell apoptosis was evaluated by detecting apoptotic rate, caspase-3/7 activity, and Bcl-2 and Bax expression. KEY FINDINGS: The results demonstrated Linc00152 was up-regulated in clinical IH tissues and HemECs. Knockdown of Linc00152 in HemECs suppressed the activation of Akt/mTOR and Notch1 signaling pathways and caused reduction in cell proliferation and Ki67 expression in HemECs. Besides, Linc00152 knockdown resulted in a significant increase in apoptotic rate, caspase-3/7 activity, and Bax expression level, as well as a decrease in Bcl-2 expression level. However, the effects of Linc00152 knockdown on cell proliferation and apoptosis were mitigated by overexpression of Akt or Notch1. SIGNIFICANCE: Knockdown of Linc00152 suppressed HemECs proliferation and induced apoptosis via inhibiting Akt/mTOR and Notch1 signaling pathways.


Assuntos
Células Endoteliais/metabolismo , Técnicas de Silenciamento de Genes , Hemangioma/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/genética , Receptor Notch1/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Pré-Escolar , Feminino , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Lactente , Masculino , RNA Longo não Codificante/antagonistas & inibidores , Transdução de Sinais/genética , Regulação para Cima
12.
Cell Struct Funct ; 44(1): 41-50, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30713220

RESUMO

Infantile hemangioma is the most common soft tissue tumors in childhood. In clinic, propranolol is widely used for infantile hemangioma therapy. However, some of the infantile hemangioma patients display resistance to propranolol treatment. Previous studies show that miR-187-3p is inhibited in hepatocellular carcinoma and lung cancer, while the role of miR-187-3p in infantile hemangioma remains unclear. In the present study, we explore the biological role of miR-187-3p in infantile hemangioma. The mRNA and protein levels of related genes were detected by real-time PCR and Western blotting. CCK8 assay was used to detect cell viability and IC50 values of propranolol. Cell apoptosis was detected by Caspase-3 Activity assay. Luciferase reporter assay and biotin RNA pull down assay were used to detect the interaction between miR-187-3p and the targeted gene. MiR-187-3p was down-regulated in infantile hemangioma tissues and promoted propranolol sensitivity of HemSCs. Mechanically, NIPBL was the direct target of miR-187-3p in HemSCs. NIPBL downregulation inhibited propranolol resistance of HemSCs. Re-introduction of NIPBL reversed miR-187-3p-meidated higher propranolol sensitivity of HemSCs. MiR-187-3p enhanced propranolol sensitivity of hemangioma stem cells via targeting NIPBL. MiR-187-3p may serve as a novel prognostic indicator and potential target for infantile hemangioma therapy.Key words: MiR-187-3p, infantile hemangioma, propranolol, resistance, NIPBL.


Assuntos
Hemangioma/genética , Hemangioma/patologia , MicroRNAs/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Propranolol/farmacologia , Sequência de Bases , Proteínas de Ciclo Celular , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Lactente , Células-Tronco Neoplásicas/patologia , Proteínas/genética
13.
JAMA Dermatol ; 155(2): 211-215, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30601876

RESUMO

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.


Assuntos
Hemangioma/genética , Hemangioma/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação de Sentido Incorreto , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adulto , Fatores Etários , Idoso , Boston , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Medição de Risco , Amostragem , Fatores Sexuais , Inclusão do Tecido
14.
Vascul Pharmacol ; 112: 91-101, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30342234

RESUMO

Vascular endothelial growth factors regulate vascular and lymphatic growth. Dysregulation of VEGF signaling is connected to many pathological states, including hemangiomas, arteriovenous malformations and placental abnormalities. In heart, VEGF gene transfer induces myocardial angiogenesis. Besides vascular and lymphatic endothelial cells, VEGFs affect multiple other cell types. Understanding VEGF biology and its paracrine signaling properties will offer new targets for novel treatments of several diseases.


Assuntos
Malformações Arteriovenosas/metabolismo , Células Endoteliais/metabolismo , Cardiopatias/metabolismo , Hemangioma/metabolismo , Miocárdio/metabolismo , Placenta/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Malformações Arteriovenosas/genética , Malformações Arteriovenosas/patologia , Células Endoteliais/patologia , Feminino , Cardiopatias/patologia , Hemangioma/genética , Hemangioma/patologia , Humanos , Linfangiogênese , Miocárdio/patologia , Neovascularização Patológica , Neovascularização Fisiológica , Comunicação Parácrina , Placenta/patologia , Gravidez , Transdução de Sinais , Fator A de Crescimento do Endotélio Vascular/genética
15.
Pediatr Dev Pathol ; 22(3): 236-242, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30428272

RESUMO

INTRODUCTION: Chorangioma (CA) is the most common nontrophoblastic, vascular tumor-like lesion of the placenta with a reported incidence of 0.5% to 1% in all examined placentas. The underlying molecular mechanisms of CAs are still poorly elucidated, and a systematic investigation of the genetic background of CAs has not previously been done. MATERIALS AND METHODS: Tissue biopsies from 8 large (>40 mm) histologically confirmed CAs and 8 unaffected matched placenta controls, along with standard control DNA samples were analyzed for large genomic deletions and duplications using array comparative genomic hybridization (array-CGH) method. RESULTS: Array-CGH analysis revealed no rare or novel copy number variants in the CA samples compared with either standard control DNA or unaffected placenta DNA from the same individual. DISCUSSION: In this study, a systematic genetic investigation of 8 large CAs failed to demonstrate any large-scale pathogenic genetic changes. This lack of association might support a nongenetic, nontumorous origin of these lesions; however, additional genetic studies focusing on smaller genomic alterations are required to fully assess any possible genetic contribution.


Assuntos
Variações do Número de Cópias de DNA/genética , Hemangioma/genética , Hibridização Genômica Comparativa , Feminino , Testes Genéticos , Idade Gestacional , Hemangioma/patologia , Humanos , Placenta/patologia , Gravidez , Duplicações Segmentares Genômicas/genética , Deleção de Sequência
16.
JAMA Ophthalmol ; 137(1): 91-95, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30422215

RESUMO

Importance: Choroidal hemangiomas are defined by a thickened choroid owing to vessel overgrowth, which may increase the intraocular pressure and lead to glaucoma. Choroidal hemangioma and glaucoma often co-occur in patients with Sturge-Weber syndrome, a rare neurocutaneous disorder characterized by capillary malformations. Objective: To determine whether the mutation found in most capillary malformations, GNAQ R183Q (c.548G>A), was present in the choroidal hemangioma of a patient with Sturge-Weber syndrome. Design, Setting, and Participant: Using laser-capture microdissection, choroidal blood vessels were isolated from paraffin-embedded tissue sections, and genomic DNA was extracted for mutational analysis. Choroidal sections were analyzed in parallel. A patient with choroidal hemangioma and Sturge-Weber syndrome who had undergone enucleation was analyzed in this study at Boston Children's Hospital. Negative controls were choroidal tissue from an eye with retinoblastoma and unaffected lung tissue; brain tissue from a different patient with Sturge-Weber syndrome served as a positive control. Infantile hemangioma was analyzed as well. Data were analyzed in 2018. Main Outcomes and Measures: The mutant allelic frequency of GNAQ R183 and GNAQ Q209L/H/P was determined by droplet digital polymerase chain reaction on isolated genomic DNA. The infantile hemangioma marker glucose transporter-1 was visualized by immunofluorescent staining of tissue sections. Results: The GNAQ R183Q mutation was present in the patient's choroidal vessels (21.1%) at a frequency similar to that found in brain tissue from a different patient with Sturge-Weber syndrome (25.1%). In contrast, choroidal vessels from a case of retinoblastoma were negative for the mutation (0.5%), as was lung tissue (0.2%). The patient's choroidal tissue was negative for the 3 GNAQ mutations associated with congenital hemangioma and for the infantile hemangioma marker glucose transporter-1. Conclusions and Relevance: The results suggest that a more accurate description for choroidal hemangioma in patients with Sturge-Weber syndrome is choroidal capillary malformation. This finding may explain why propranolol, used to treat infantile hemangiomas, has been largely ineffective in patients with choroidal hemangioma. Further studies are needed to corroborate this finding.


Assuntos
Capilares/anormalidades , Neoplasias da Coroide/genética , Corioide/irrigação sanguínea , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Hemangioma/genética , Mutação , Polimorfismo de Nucleotídeo Único , Síndrome de Sturge-Weber/genética , Malformações Vasculares/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Coroide/metabolismo , Análise Mutacional de DNA , Técnica Indireta de Fluorescência para Anticorpo , Transportador de Glucose Tipo 1/metabolismo , Hemangioma/metabolismo , Humanos , Lactente , Reação em Cadeia da Polimerase , Síndrome de Sturge-Weber/metabolismo
17.
Ophthalmology ; 126(5): 759-763, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30537484

RESUMO

PURPOSE: GNAQ mutations have been identified in port wine stains (both syndromic and nonsyndromic) and melanocytic ocular neoplasms. This study investigates the presence of GNAQ mutations in diffuse (those associated with Sturge-Weber syndrome [SWS]) and solitary choroidal hemangiomas. PARTICIPANTS: Tissue from 11 patients with the following diagnoses: port wine stain (n = 3), diffuse choroidal hemangioma (n = 1), solitary choroidal hemangioma (n = 6), and choroidal nevus (n = 1). METHODS: Ten specimens were interrogated with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, a hybridization capture-based next-generation sequencing assay for targeted deep sequencing of all exons and selected introns of 468 key cancer genes in formalin-fixed, paraffin-embedded tumors. Digital polymerase chain reaction was used to detect GNAQ Q209 mutation in 1 specimen. MAIN OUTCOME MEASURES: Detection of GNAQ codon-specific mutation. RESULTS: Activating somatic GNAQ mutations (c.547C > T; p.Arg183Cys) were found in 100% (3 of 3) of the port wine stain and in the diffuse choroidal hemangioma. Somatic GNAQ mutations (c.626A > T; p.Gln209Leu) were found in 100% (6 of 6) of the solitary choroidal hemangiomas and (c.626A > C; p.Gln209Pro) in the choroidal nevus. CONCLUSIONS: GNAQ mutations occur in both diffuse and solitary hemangiomas, although at distinct codons. An R183 codon is mutant in diffuse choroidal hemangiomas, consistent with other Sturge-Weber vascular malformations. By contrast, solitary choroidal hemangiomas have mutations in the Q209 codon, similar to other intraocular melanocytic neoplasms.


Assuntos
Neoplasias da Coroide/genética , DNA de Neoplasias/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Hemangioma/genética , Mutação , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Corioide/patologia , Neoplasias da Coroide/diagnóstico , Neoplasias da Coroide/metabolismo , Análise Mutacional de DNA , Feminino , Seguimentos , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Hemangioma/diagnóstico , Hemangioma/metabolismo , Humanos , Masculino , Estudos Retrospectivos
18.
Cell Physiol Biochem ; 51(6): 2872-2886, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30562741

RESUMO

BACKGROUND/AIMS: Dysregulation of long noncoding RNAs (lncRNAs) is associated with the proliferation and metastasis in a variety of cancers, of which lncRNA maternally expressed gene 3 (MEG3) has been indicated as a tumor suppressor in multiple malignancies. However, the underlying mechanisms by which MEG3 contributes to human hemangiomas (HAs) remain undetermined. METHODS: qRT-PCR analysis was performed to examine the expression levels of MEG3 and VEGF in proliferating or involuting phase HAs. MTT, colony formation assay, flow cytometry analysis and a subcutaneous xenograft tumor model were conducted to assess the effects of MEG3 on the HAs tumorigenesis. The interaction between MEG3 and miRNAs or their downstream pathways was evidenced by bioinformatic analysis, luciferase report assays, RNA immunoprecipitation (RIP) assay. and Western blot analysis. RESULTS: The expression of MEG3 was substantially decreased and had a negative correlation with VEGF expression in proliferating phase HAs, as compared with the involuting phase HAs and normal skin tissues. Ectopic expression of MEG3 suppressed cell proliferation, colony formation and induced cycle arrest in vitro and in vivo, followed by the downregulation of VEGF and cyclinD1, but knockdown of MEG3 reversed these effects. Furthermore, MEG3 was verified to act as a sponge of miR-494 in HAs cells, and miR-494 counteracted MEG3-caused anti-proliferative effects by regulating PTEN/PI3K/AKT pathway, and exhibited the negative correlation with MEG3 and PTEN expression in proliferating phase HAs. CONCLUSION: Our findings suggested that lncRNA MEG3 inhibited HAs tumorigenesis by sponging miR-494 and regulating PTEN/PI3K/AKT pathway.


Assuntos
Carcinogênese/genética , Regulação Neoplásica da Expressão Gênica , Hemangioma/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Feminino , Hemangioma/patologia , Humanos , Camundongos Endogâmicos BALB C , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Tumorais Cultivadas
19.
Mol Med Rep ; 18(4): 4065-4071, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30132564

RESUMO

Hemangioma (HA) is a type of benign tumor common in infancy. The main feature of HA is the abnormal proliferation of vascular endothelial cells. To date, the pathogenesis of HA remains unclear. Fully understanding the process of HA tumorigenesis is essential for developing novel treatment for HAs. Dysregulation of microRNAs (miRNAs/miR) has been reported to be involved in the development of various diseases, including HA. In the present study, the expression of miR­424 decreased in HA­derived endothelial cells (HemECs). To elucidate the role of miR­424 in HAs development, the present study overexpressed or inhibited miR­424 in HemECs, revealing that miR­424 overexpression significantly inhibited HemEC growth and promoted apoptosis, while the downregulation of miR­424 promoted cell growth and inhibited cell apoptosis. To elucidate the underlying mechanism, bioinformatic analyses were performed, the result of which demonstrated that the 3'­untranslated region of vascular endothelial growth factor receptor 2 (VEGFR­2) may be a target of miR­424. The result of a dual luciferase reporter assay confirmed that the expression of VEGFR­2 was inhibited by miR­424. In addition, it was revealed that the hyper­phosphorylation of protein kinase B (AKT) and extracellular signal­regulated kinase (ERK) in HemECs, and the restoration of miR­424 markedly inhibited the activation of AKT and ERK. In conclusion, these results indicated that miR­424 may target VEGFR­2 and inhibit HemECs growth, and that low expression of miR­424 in HemECs may lead to an increase in cell growth and a decrease in cell apoptosis. Thus, it was proposed that miR­424 may serve as a tumor suppressor in HemECs, and that VEGFR­2 may be a potential tumor suppressive target in HemECs and for the treatment of HA.


Assuntos
Células Endoteliais/metabolismo , Células Endoteliais/patologia , Hemangioma/genética , Hemangioma/patologia , MicroRNAs/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Apoptose/genética , Sequência de Bases , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , MicroRNAs/genética , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
20.
Am J Med Genet A ; 176(9): 1996-2003, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30055085

RESUMO

Non-immune hydrops fetalis (NIHF) is the abnormal accumulation of serous fluid in more than two fetal or neonatal interstitial spaces due to nonimmune causes. It is a serious condition that requires extensive medical care as it indicates severe fetal compromise. We clinically evaluated four patients from two branches of a highly consanguineous family from the UAE with NIHF using whole exome sequencing and in silico analysis. Fetal onset pleural and peritoneal effusions were detected in all four patients and were born with moderate to severe hydrops fetalis that resolved with age. Follow up showed relatively normal growth and development apart from mild ascites and haemangiomas in all affected children, recurrent hydrocele in all affected males, intestinal malabsorption in two patients, dysmorphic features in two patients, and congenital cardiac defects in three out of four patients. Molecular testing identified a homozygous eight nucleotide deletion in THSD1 gene (NM_199263:c.1163_1170delGGCCAGCC, p.Arg388Glnfs*66) as the underlying cause of this phenotype in the affected children. The novel variant cosegregates with the described phenotype in an autosomal recessive mode of inheritance and is predicted to be pathogenic as it leads to a truncated protein that lost important structural and functional domains. Thrombospondin-1 domain containing protein 1 gene THSD1 has been recently associated with of NIHF and embryonic lethality. Here, we report the novel truncating THSD1 variant, and describe new clinical features that have not been reported previously thus expanding the phenotype associate with loss-of-function mutations in THSD1 causing NIHF.


Assuntos
Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/genética , Hemangioma/diagnóstico , Hemangioma/genética , Hidropisia Fetal/diagnóstico , Hidropisia Fetal/genética , Mutação , Trombospondinas/genética , Alelos , Pré-Escolar , Biologia Computacional/métodos , Consanguinidade , Análise Mutacional de DNA , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Lactente , Masculino , Análise de Sequência de DNA , Síndrome , Sequenciamento Completo do Exoma
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