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1.
Anticancer Res ; 40(10): 5437-5443, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988865

RESUMO

BACKGROUND: Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor A (VEGFA), and has been reported to be overexpressed in several malignancies. Since angiogenesis plays an important role in pathogenesis of multiple myeloma (MM) and the role of NRP1 in MM has not been studied yet, we characterized the expression of NRP1 in this disease. MATERIALS AND METHODS: The expression level of NRP1 was measured in 140 patients newly diagnosed with MM and 28 healthy controls by flow cytometry and quantitative reverse transcriptase polymerase chain reaction. RESULTS: Expression of NRP1 was significantly reduced on plasma cells (median=2.05%) compared to that on B-cells (median=10.05%, p<0.0001) in bone marrow of patients with MM. In MM, the expression of NRP1 was high on plasmacytoid dendritic cells (median=85.85%) and low on regulatory T-cells (median=0.6%). CONCLUSION: In MM, NRP1 is regulated differentially as compared to other B-cell malignancies at both the RNA and protein level.


Assuntos
Mieloma Múltiplo/genética , Neovascularização Patológica/genética , Neuropilina-1/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Linfócitos B/metabolismo , Feminino , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Neovascularização Patológica/sangue , Neovascularização Patológica/patologia , Neuropilina-1/sangue , Transdução de Sinais/genética
2.
Anticancer Res ; 40(10): 5463-5469, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988868

RESUMO

BACKGROUND/AIM: Periostin exists as an extracellular matrix protein in several carcinomas and is related to metastasis and poor prognosis. It is mainly secreted from cancer associated fibroblasts, and not from carcinoma cells. As a tumor microenvironment component, periostin usually mediates tumor cell stemness, metastasis, angiogenesis and lymphangiogenesis. This study aimed to examine the role of periostin in chondrosarcoma. MATERIALS AND METHODS: To evaluate the effect of periostin on the proliferation of chondrosarcoma cells, MTT assay was performed on SW1353 cells and periostin knockdown SW1353 cells. Migration activity was examined using Boyden chamber. RESULTS: Periostin, secreted from chondrosarcoma cells, was found to support proliferation, and maintain stemness and migration of chondrosarcoma cells. Periostin also induced proliferation and migration of lymphatic endothelial cells. CONCLUSION: Periostin plays an important role in chondrosarcoma development and disease progression.


Assuntos
Moléculas de Adesão Celular/genética , Proliferação de Células/genética , Condrossarcoma/genética , Neovascularização Patológica/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Sobrevivência Celular/genética , Condrossarcoma/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Linfangiogênese/genética , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
3.
PLoS Pathog ; 16(8): e1008730, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776977

RESUMO

Kaposi's sarcoma (KS), caused by Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angioproliferative disseminated tumor of endothelial cells commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) mediates KSHV-induced cell motility (PLoS Pathog. 2019 Jan 30;15(1):e1007578). However, the role of vIRF1 in KSHV-induced cellular transformation and angiogenesis remains unknown. Here, we show that vIRF1 promotes angiogenesis by upregulating sperm associated antigen 9 (SPAG9) using two in vivo angiogenesis models including the chick chorioallantoic membrane assay (CAM) and the matrigel plug angiogenesis assay in mice. Mechanistically, vIRF1 interacts with transcription factor Lef1 to promote SPAG9 transcription. vIRF1-induced SPAG9 promotes the interaction of mitogen-activated protein kinase kinase 4 (MKK4) with JNK1/2 to increase their phosphorylation, resulting in enhanced VEGFA expression, angiogenesis, cell proliferation and migration. Finally, genetic deletion of ORF-K9 from KSHV genome abolishes KSHV-induced cellular transformation and impairs angiogenesis. Our results reveal that vIRF1 transcriptionally activates SPAG9 expression to promote angiogenesis and tumorigenesis via activating JNK/VEGFA signaling. These novel findings define the mechanism of KSHV induction of the SPAG9/JNK/VEGFA pathway and establish the scientific basis for targeting this pathway for treating KSHV-associated cancers.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Herpesvirus Humano 8/metabolismo , Fatores Reguladores de Interferon/metabolismo , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , Sarcoma de Kaposi/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteínas Virais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Transformação Celular Neoplásica , Herpesvirus Humano 8/genética , Interações Hospedeiro-Patógeno , Humanos , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/genética , Proteína Quinase 9 Ativada por Mitógeno/genética , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Sarcoma de Kaposi/genética , Sarcoma de Kaposi/fisiopatologia , Sarcoma de Kaposi/virologia , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas Virais/genética
4.
Nat Commun ; 11(1): 3571, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32678094

RESUMO

Pathogenic bacteria of the genus Bartonella can induce vasoproliferative lesions during infection. The underlying mechanisms are unclear, but involve secretion of an unidentified mitogenic factor. Here, we use functional transposon-mutant screening in Bartonella henselae to identify such factor as a pro-angiogenic autotransporter, called BafA. The passenger domain of BafA induces cell proliferation, tube formation and sprouting of microvessels, and drives angiogenesis in mice. BafA interacts with vascular endothelial growth factor (VEGF) receptor-2 and activates the downstream signaling pathway, suggesting that BafA functions as a VEGF analog. A BafA homolog from a related pathogen, Bartonella quintana, is also functional. Our work unveils the mechanistic basis of vasoproliferative lesions observed in bartonellosis, and we propose BafA as a key pathogenic factor contributing to bacterial spread and host adaptation.


Assuntos
Bartonella/patogenicidade , Neovascularização Patológica/metabolismo , Transdução de Sinais , Sistemas de Secreção Tipo V/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Virulência/metabolismo , Animais , Bartonella/classificação , Bartonella/genética , Proliferação de Células , Perfilação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/microbiologia , Humanos , Camundongos , Neovascularização Patológica/genética , Neovascularização Patológica/microbiologia , Domínios Proteicos , Sistemas de Secreção Tipo V/química , Sistemas de Secreção Tipo V/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Fatores de Virulência/química , Fatores de Virulência/genética
5.
Cancer Sci ; 111(9): 3245-3257, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32639636

RESUMO

Because advanced laryngeal squamous cell carcinoma (LSCC) is diagnosed as a malignant tumor with a poor prognosis, the associated mechanisms still need to be further investigated. As key players in the development and progression of LSCC, lncRNAs have attracted increasing attention from many researchers. In this study, a novel lncRNA termed IGKJ2-MALLP2 was identified and investigated for its effects on the development of LSCC. IGKJ2-MALLP2 expression was confirmed by RT-qPCR in 78 pairs of tissues and human laryngeal carcinoma cell lines. The results of this study showed that the expression of IGKJ2-MALLP2 was reduced in LSCC tissues and displayed close relationships with tumor stage, lymph node metastasis, and clinical stage. Using a dual-luciferase reporter assay, the ability of miR-1911-3p to bind both IGKJ2-MALLP2 and p21 mRNA was demonstrated. IGKJ2-MALLP2 could upregulate p21 expression by competitively binding miR-1911-3p. Moreover, IGKJ2-MALLP2 effectively hindered the invasion, migration, and proliferation of AMC-HN-8 and TU212 tumor cells. Furthermore, its high expression could hinder the secretion of VEGF-A and suppress angiogenesis. As revealed by the results of in vitro experiments, IGKJ2-MALLP2 overexpression could restrict tumor growth and blood vessel formation in a xenograft model of LSCC. As indicated from the mentioned findings, IGKJ2-MALLP2, which mediates p21 expression by targeting miR-1911-3p, was capable of regulating LSCC progression and could act as an underlying therapeutic candidate to treat LSCC.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias Laríngeas/genética , MicroRNAs , Neovascularização Patológica/genética , Interferência de RNA , RNA Longo não Codificante , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Regiões 3' não Traduzidas , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 258: 118094, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32673663

RESUMO

AIMS: Docosahexaenoic acid (DHA) as an omega 3 free fatty acid has been reported to exert anti-angiogenesis effects. However, our current understanding regarding the precise mechanisms of such effects is still limited. Exosomes secreted by cancer cells may act as angiogenesis promoters. The aim of the study was to determine altered expression levels of HIF-1α, TGF-ß, VEGFR, Snail1, Snail2 and SOX2 and their regulating microRNAs in MDA-MB-231 and BT-474 cell lines after treatment with DHA in both normoxic and hypoxic conditions. MAIN METHODS: Human breast cancer cell lines including MDA-MB-231 and BT-474 were treated for 24 h with 100 uM DHA under normoxic and hypoxic conditions. Exosomes were isolated from untreated and treated cells and characterized by transmission electron microscopy (TEM) and western blotting. RNAs from cells and isolated exosomes were extracted and cDNAs were synthesized. Expression levels of miRNAs and their pro-angiogenic target genes were analyzed using quantitative real-time PCR (qRT-PCR). KEY FINDINGS: We showed significant decrease in the expression of pro-angiogenic genes including HIF1-α, TGF-ß, SOX2, Snail1, Snail2 and VEGFR in cells and also their secreted exosomes after treatment with DHA in normoxic and hypoxic conditions. Also the expression levels of tumor suppressor miRs including miR-101, miR-199, miR-342 were increased and the expression levels of oncomiRs including mir-382 and miR-21 were decreased after treatment with DHA in cells and exosomes. SIGNIFICANCE: DHA can alter the expression of pro-angiogenic genes and microRNA contents in breast cancer cells and their derived-exosomes in favor of the inhibition of angiogenesis. Our data demonstrated new insight into DHA's anti-cancer action to target not only breast cancer cells but also their derived exosomes to suppress tumor angiogenesis.


Assuntos
Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Ácidos Docosa-Hexaenoicos/farmacologia , Regulação para Baixo , Exossomos/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/ultraestrutura , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , MicroRNAs/metabolismo
7.
Nat Commun ; 11(1): 2709, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483169

RESUMO

Aberrant immune responses including reactive phagocytes are implicated in the etiology of age-related macular degeneration (AMD), a major cause of blindness in the elderly. The translocator protein (18 kDa) (TSPO) is described as a biomarker for reactive gliosis, but its biological functions in retinal diseases remain elusive. Here, we report that tamoxifen-induced conditional deletion of TSPO in resident microglia using Cx3cr1CreERT2:TSPOfl/fl mice or targeting the protein with the synthetic ligand XBD173 prevents reactivity of phagocytes in the laser-induced mouse model of neovascular AMD. Concomitantly, the subsequent neoangiogenesis and vascular leakage are prevented by TSPO knockout or XBD173 treatment. Using different NADPH oxidase-deficient mice, we show that TSPO is a key regulator of NOX1-dependent neurotoxic ROS production in the retina. These data define a distinct role for TSPO in retinal phagocyte reactivity and highlight the protein as a drug target for immunomodulatory and antioxidant therapies for AMD.


Assuntos
NADPH Oxidase 1/genética , Neovascularização Patológica/genética , Fagócitos/metabolismo , Receptores de GABA/genética , Degeneração Macular Exsudativa/genética , Animais , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , NADPH Oxidase 1/metabolismo , Neovascularização Patológica/metabolismo , Fagócitos/efeitos dos fármacos , Purinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de GABA/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Degeneração Macular Exsudativa/metabolismo
8.
Gene ; 754: 144851, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525044

RESUMO

Tumor angiogenesis is a common feature of rapidly growing solid tumors, accelerated by tumor hypoxia. It is associated with subsequent metastasis, progression, poor prognosis, and aggressive phenotype in many types of cancer. The hypoxia-inducible factors/vascular endothelial growth factor 1(HIF1/VEGF) signal pathway plays an important role in tumor angiogenesis. Proteasome-mediated ubiquitin degradation pathway is one of the most important processes involved in regulating the level of cellular HIF-1α. Our study revealed that Histone Deacetylase 1 (HDAC1) directly inhibits the ubiquitination of HIF1α. Additionally, HDAC1 activates HIF1α/VEGFA signaling pathway, promoting s tumor angiogenesis. These findings have enhanced our understanding of the molecular mechanisms of colorectal (CRC) tumor angiogenesis. HDAC1/HIF1α/VEGFA signaling pathway may provide a novel therapeutic window for CRC.


Assuntos
Neoplasias Colorretais/patologia , Regulação Neoplásica da Expressão Gênica , Histona Desacetilase 1/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neovascularização Patológica/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Ciclo Celular , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Progressão da Doença , Histona Desacetilase 1/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Nus , Invasividade Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Prognóstico , Transdução de Sinais , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Life Sci ; 256: 117888, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32497630

RESUMO

AIMS: The dysregulation of circular RNAs (circRNAs) has been implicated in the progression of diabetic retinopathy (DR). This study aims to explore the role and underlying mechanism of hsa_circ_0081108 (circCOL1A2) in DR. MATERIALS AND METHODS: circCOL1A2, vascular endothelial growth factor (VEGF) and miR-29b expression levels in human retinal microvascular endothelial cells (hRMECs) were detected by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting. The biological functions of hRMECs were evaluated by MTT, transwell, tube formation, and vascular permeability assays, respectively. The interaction between miR-29b and circCOL1A2/VEGF was determined by dual luciferase assay. The release of VEGF was examined by ELISA. The in vivo role of circCOL1A2 was further verified in streptozotocin (STZ)-induced DR in mice. The pathological changes and VEGF expression in retinal tissues were detected by hematoxylin and eosin (HE) and immunohistochemical staining. KEY FINDINGS: High glucose (HG) challenge led to increased circCOL1A2, VEGF, MMP-2, MMP-9 levels, but decreased miR-29b level in hRMECs. In addition, circCOL1A2 sponged miR-29b to promote VEGF expression. Silencing of circCOL1A2 inhibited HG-induced proliferation, migration, angiogenesis and vascular permeability of hRMECs via enhancing miR-29b expression. Moreover, circCOL1A2/miR-29b axis participated in HG-induced increase in angiogenesis-related protein expression. Finally, circCOL1A2 knockdown suppressed angiogenesis via regulating miR-29b/VEGF axis in DR mice. SIGNIFICANCE: circCOL1A2 facilities angiogenesis during the pathological progression of DR via regulating miR-29b/VEGF axis, suggesting that targeting circCOL1A2 may be a potential treatment for DR.


Assuntos
Retinopatia Diabética/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Neovascularização Patológica/genética , RNA Circular/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Animais , Sequência de Bases , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Glucose/toxicidade , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Microvasos/patologia , Modelos Biológicos , RNA Circular/genética , Retina/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
DNA Cell Biol ; 39(6): 1041-1050, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32401536

RESUMO

Ovarian cancer (OC) is one of gynecological malignancies that seriously affects women's health. Mounting evidence demonstrated that long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs) play important roles in various biological processes related to the pathogenesis of OC. This research aimed to investigate the regulatory mechanism of lncRNA SCAMP1/miR-137/CXCL12 (C-X-C motif chemokine ligand 12) axis on OC progression. In this study, we found that SCAMP1 was highly expressed in OC cells, which promoted OC cell invasion and angiogenesis. In addition, our research confirmed that SCAMP1 could bind with miR-137, and SCAMP1 sponged miR-137 to accelerate the progression of OC. We also observed that CXCL12 was a downstream target gene for miR-137, and miR-137 targeted CXCL12 to participate in the regulation of OC. Finally, through TCGA database, we found that SCAMP1 (or CXCL12) was upregulated as well as miR-137 was downregulated in OC tissues, and high (or low) level of them was associated with poor prognosis. miR-137 expression was negatively correlated with SCAMP1 (or CXCL12) expression, and SCAMP1 expression was positively correlated with CXCL12 expression in OC. In summary, our study clarified the role of SCAMP1/miR-137/CXCL12 axis in OC, and this finding may provide a potential therapeutic target of OC.


Assuntos
Quimiocina CXCL12/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias Ovarianas/patologia , RNA Longo não Codificante/genética , Proteínas de Transporte Vesicular/genética , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Invasividade Neoplásica/genética , Neoplasias Ovarianas/irrigação sanguínea , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Prognóstico
11.
Ann Rheum Dis ; 79(7): 891-900, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381568

RESUMO

OBJECTIVES: To decipher the phenotype of endothelial cells (ECs) derived from circulating progenitors issued from patients with rheumatoid arthritis (RA). METHODS: RA and control ECs were compared according to their proliferative capacities, apoptotic profile, response to tumour necrosis factor (TNF)-α stimulation and angiogenic properties. Microarray experiments were performed to identify gene candidates relevant to pathological angiogenesis. Identified candidates were detected by RT-PCR and western blot analysis in ECs and by immunohistochemistry in the synovium. Their functional relevance was then evaluated in vitro after gene invalidation by small interfering RNA and adenoviral gene overexpression, and in vivo in the mouse model of methyl-bovine serum albumin-(mBSA)-induced arthritis. RESULTS: RA ECs displayed higher proliferation rate, greater sensitisation to TNF-α and enhanced in vitro and in vivo angiogenic capacities. Microarray analyses identified the NAD-dependent protein deacetylase sirtuin-1 (SIRT1) as a relevant gene candidate. Decreased SIRT1 expression was detected in RA ECs and synovial vessels. Deficient endothelial SIRT1 expression promoted a proliferative, proapoptotic and activated state of ECs through the acetylation of p53 and p65, and lead the development of proangiogenic capacities through the upregulation of the matricellular protein cysteine-rich angiogenic protein-61. Conditional deletion of SIRT1 in ECs delayed the resolution of experimental methyl-bovine serum albumin-(mBSA)-induced arthritis. Conversely, SIRT1 activation reversed the pathological phenotype of RA ECs and alleviates signs of experimental mBSA-induced arthritis. CONCLUSIONS: These results support a role of SIRT1 in RA and may have therapeutic implications, since targeting angiogenesis, and especially SIRT1, might be used as a complementary therapeutic approach in RA.


Assuntos
Artrite Reumatoide/genética , Neovascularização Patológica/genética , Sirtuína 1/metabolismo , Membrana Sinovial/irrigação sanguínea , Adulto , Animais , Apoptose/genética , Artrite Experimental , Artrite Reumatoide/patologia , Proliferação de Células/genética , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neovascularização Patológica/patologia , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/genética
12.
Toxicol Appl Pharmacol ; 395: 114977, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32234386

RESUMO

Plastic in the ocean degrades to microplastic, thereby enhancing the leaching of incorporated plasticizers due to the increased particle surface. The uptake of microplastic-derived plasticizers by marine animals and the subsequent entry in the food chain raises concerns for adverse health effects in human beings. Frequently used plasticizers as the organophosphate ester tri-o-cresyl phosphate (TOCP) are known to affect the male reproductive system. However, the overall endocrine potential of TOCP and the underlying molecular mechanisms remain elusive as yet. In this study, we investigated the molecular effects of TOCP on estrogen receptor α (ERα)-transfected HEK-ESR1 cells and the human breast cancer cell line MCF-7. Applying virtual screening and molecular docking, we identified TOCP as potent ligand of ERα in silico. Microscale thermophoresis confirmed the binding in vitro with similar intensity as the natural ligand 17-ß-estradiol. To identify the molecular mechanisms of TOCP-mediated effects, we used next-generation sequencing to analyze the gene expression pattern of TOCP-treated MCF-7 cells. RNA-sequencing revealed 22 differently expressed genes associated with ESR1 as upstream regulator: CYP1A1, SLC7A11, RUNX2, DDIT4, STC2, KLHL24, CCNG2, CEACAM5, SLC7A2, MAP1B, SLC7A5, IGF1R, CD55, FOSL2, VEGFA, and HSPA13 were upregulated and PRKCD, CCNE1, CEBPA, SFPQ, TNFAIP2, KRT19 were downregulated. The affected genes promote tumor growth by increasing angiogenesis and nutritional supply, favor invasion and metastasis, and interfere with the cell cycle. Based on the gene expression pattern, we conclude TOCP to mediate endocrine effects on MCF-7 cells by interacting with ERα.


Assuntos
Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/efeitos dos fármacos , Plastificantes/toxicidade , Tritolil Fosfatos/toxicidade , Neoplasias da Mama/genética , Ciclo Celular/genética , Disruptores Endócrinos , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Células MCF-7 , Masculino , Modelos Moleculares , Simulação de Acoplamento Molecular , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Neovascularização Patológica/genética , RNA/química , Transfecção , Tritolil Fosfatos/metabolismo
13.
J Cancer Res Clin Oncol ; 146(7): 1647-1658, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32335720

RESUMO

BACKGROUND: Additional prognostic factors and personalized therapeutic alternatives for vulvar squamous cell carcinoma (VSCC), especially for advanced stages with poor prognosis, are urgently needed. OBJECTIVES: To review and assess literature regarding underlying molecular mechanisms of VSCC target therapeutic and prognostic approaches. METHODS: We performed a narrative literature review from the inception of the database up to January 2020 limited to English language, organizing knowledge in five main fields: extracellular and intracellular cell cycle deregulation, tumor immune microenvironment, tumor angiogenesis and hormones. RESULTS: EGFR immunohistochemical overexpression/gene amplification, representing early events in VSCC carcinogenesis, have been correlated with a worse prognosis and led to inclusion of erlotinib in cancer guidelines. p16 expression and HPV positivity are linked to a better prognosis, while p53 overexpression is linked to a worse prognosis; thus, biomarkers could help tailoring conventional treatment and follow-up. The implications of PD-L1 positivity in reference to HPV status and prognosis are still not clear, even though pembrolizumab is part of available systemic therapies. The role of tumor angiogenesis emerges through data on microvessel density, immunohistochemical VEGF staining and evaluation of serum VEGF concentrations. Few data exist on hormonal receptor expression, even though hormonal therapy showed great manageability. CONCLUSIONS: We suggest adding p16, p53 and HPV status to routine hystopathological examination of vulvar biopsies or surgical specimens. Predictive biomarkers for anti-EGFR and anti-PD-1/PD-L1 drugs are needed. Enough preclinical data supporting anti-angiogenic target therapies in clinical trials are existing. Hormonal receptor expression deserves further investigation.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Ciclo Celular/genética , Tomada de Decisão Clínica , Suscetibilidade a Doenças , Espaço Extracelular/metabolismo , Feminino , Humanos , Espaço Intracelular/metabolismo , Terapia de Alvo Molecular , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologia
14.
Life Sci ; 252: 117647, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32275935

RESUMO

Approximately 98% of the human genome consists of non-coding sequences that are classified into two classes by size: small non-coding RNAs (≤200 nucleotides) and long non-coding RNAs (≥200 nucleotides). Long non-coding RNAs (lncRNAs) are involved in various cellular events and act as guides, signals, decoys, and dynamic scaffolds. Due to their oncogenic and tumor suppressive roles, lncRNAs are important in cancer development and growth. LncRNAs play their roles by modulating cancer hallmarks, including DNA damage, metastasis, immune escape, cell stemness, drug resistance, metabolic reprogramming, and angiogenesis. Angiogenesis is vital for solid tumors which guarantees their growth beyond 2 mm3. Tumor angiogenesis is a complex process and is regulated through interaction between pro-angiogenic and anti-angiogenic factors within the tumor microenvironment. There are accumulating evidence that different lncRNAs regulate tumor angiogenesis. In this paper, we described the functions and mechanisms of lncRNAs in tumor angiogenesis.


Assuntos
Neoplasias/patologia , Neovascularização Patológica/patologia , RNA Longo não Codificante/genética , Dano ao DNA/genética , Resistencia a Medicamentos Antineoplásicos , Genoma Humano , Humanos , Neoplasias/genética , Neovascularização Patológica/genética , Microambiente Tumoral/genética
15.
Proc Natl Acad Sci U S A ; 117(16): 9064-9073, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32273388

RESUMO

The invasive behavior of glioblastoma is essential to its aggressive potential. Here, we show that pleckstrin homology domain interacting protein (PHIP), acting through effects on the force transduction layer of the focal adhesion complex, drives glioblastoma motility and invasion. Immunofluorescence analysis localized PHIP to the leading edge of glioblastoma cells, together with several focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phosphorylated forms of paxillin (pPXN) and focal adhesion kinase (pFAK). Confocal microscopy specifically localized PHIP to the force transduction layer, together with TLN1 and VCL. Immunoprecipitation revealed a physical interaction between PHIP and VCL. Targeted suppression of PHIP resulted in significant down-regulation of these focal adhesion proteins, along with zyxin (ZYX), and produced profoundly disorganized stress fibers. Live-cell imaging of glioblastoma cells overexpressing a ZYX-GFP construct demonstrated a role for PHIP in regulating focal adhesion dynamics. PHIP silencing significantly suppressed the migratory and invasive capacity of glioblastoma cells, partially restored following TLN1 or ZYX cDNA overexpression. PHIP knockdown produced substantial suppression of tumor growth upon intracranial implantation, as well as significantly reduced microvessel density and secreted VEGF levels. PHIP copy number was elevated in the classical glioblastoma subtype and correlated with elevated EGFR levels. These results demonstrate PHIP's role in regulating the actin cytoskeleton, focal adhesion dynamics, and tumor cell motility, and identify PHIP as a key driver of glioblastoma migration and invasion.


Assuntos
Neoplasias Encefálicas/patologia , Adesões Focais/patologia , Glioblastoma/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neovascularização Patológica/patologia , Citoesqueleto de Actina/metabolismo , Animais , Encéfalo/patologia , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/genética , Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Estudos de Coortes , Progressão da Doença , Feminino , Dosagem de Genes , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioblastoma/irrigação sanguínea , Glioblastoma/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Microscopia Intravital , Camundongos , Microscopia Confocal , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neovascularização Patológica/genética , Imagem com Lapso de Tempo , Vinculina/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Immunol Res ; 2020: 1704631, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32190702

RESUMO

Macrophages are involved in angiogenesis, an essential process for organ growth and tissue repair, and could contribute to the pathogenesis of angiogenesis-related diseases such as malignant tumors and diabetic retinopathy. Recently, long noncoding RNAs (lncRNAs) have been proved to be important in cell differentiation, organismal development, and various diseases of pathological angiogenesis. Moreover, it has been indicated that numerous lncRNAs exhibit different functions in macrophage infiltration and polarization and regulate the secretion of inflammatory cytokines released by macrophages. Therefore, the focus of macrophage-related lncRNAs could be considered to be a potential method in therapeutic targeting angiogenesis-related diseases. This review mainly summarizes the roles played by lncRNAs which associated with macrophages in angiogenesis. The possible mechanisms of the regulatory link between lncRNAs and macrophages in various angiogenesis-related diseases were also discussed.


Assuntos
Retinopatia Diabética/genética , Macrófagos/fisiologia , Neoplasias/genética , Neovascularização Patológica/genética , RNA Longo não Codificante/genética , Animais , Citocinas/metabolismo , Retinopatia Diabética/imunologia , Humanos , Neoplasias/imunologia , Neovascularização Patológica/imunologia
17.
Biochim Biophys Acta Rev Cancer ; 1873(2): 188354, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32119940

RESUMO

Fibrillins constitute a family of large extracellular glycoproteins which multimerize to form microfibrils, an important structure in the extracellular matrix. It has long been assumed that fibrillin-2 was barely present during postnatal life, but it is now clear that fibrillin-2 molecules form the structural core of microfibrils, and are masked by an outer layer of fibrillin-1. Mutations in fibrillins give rise to heritable connective tissue disorders, including Marfan syndrome and congenital contractural arachnodactyly. Fibrillins also play an important role in matrix sequestering of members of the transforming growth factor-ß family, and in context of Marfan syndrome excessive TGF-ß activation has been observed. TGF-ß activation is highly dependent on integrin binding, including integrin αvß8 and αvß6, which are upregulated upon TGF-ß exposure. TGF-ß is also involved in tumor progression, metastasis, epithelial-to-mesenchymal transition and tumor angiogenesis. In several highly vascularized types of cancer such as hepatocellular carcinoma, a positive correlation was found between increased TGF-ß plasma concentrations and tumor vascularity. Interestingly, fibrillin-1 has a higher affinity to TGF-ß and, therefore, has a higher capacity to sequester TGF-ß compared to fibrillin-2. The previously reported downregulation of fibrillin-1 in tumor endothelium affects the fibrillin-1/fibrillin-2 ratio in the microfibrils, exposing the normally hidden fibrillin-2. We postulate that fibrillin-2 exposure in the tumor endothelium directly stimulates tumor angiogenesis by influencing TGF-ß sequestering by microfibrils, leading to a locally higher active TGF-ß concentration in the tumor microenvironment. From a therapeutic perspective, fibrillin-2 might serve as a potential target for future anti-cancer therapies.


Assuntos
Aracnodactilia/genética , Contratura/genética , Fibrilina-2/genética , Síndrome de Marfan/genética , Neoplasias/genética , Neovascularização Patológica/genética , Animais , Aracnodactilia/patologia , Tecido Conjuntivo/patologia , Contratura/patologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Fibrilina-2/metabolismo , Humanos , Síndrome de Marfan/patologia , Mutação , Neoplasias/irrigação sanguínea , Neoplasias/patologia , Neovascularização Patológica/patologia , Fator de Crescimento Transformador beta/metabolismo , Microambiente Tumoral/genética
18.
Proc Natl Acad Sci U S A ; 117(9): 4792-4801, 2020 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-32075915

RESUMO

Angiogenesis, the formation of new blood vessels, is tightly regulated by gene transcriptional programs. Yin Ying 1 (YY1) is a ubiquitously distributed transcription factor with diverse and complex biological functions; however, little is known about the cell-type-specific role of YY1 in vascular development and angiogenesis. Here we report that endothelial cell (EC)-specific YY1 deletion in mice led to embryonic lethality as a result of abnormal angiogenesis and vascular defects. Tamoxifen-inducible EC-specific YY1 knockout (YY1 iΔEC ) mice exhibited a scarcity of retinal sprouting angiogenesis with fewer endothelial tip cells. YY1 iΔEC mice also displayed severe impairment of retinal vessel maturation. In an ex vivo mouse aortic ring assay and a human EC culture system, YY1 depletion impaired endothelial sprouting and migration. Mechanistically, YY1 functions as a repressor protein of Notch signaling that controls EC tip-stalk fate determination. YY1 deficiency enhanced Notch-dependent gene expression and reduced tip cell formation. Specifically, YY1 bound to the N-terminal domain of RBPJ (recombination signal binding protein for Ig Kappa J region) and competed with the Notch coactivator MAML1 (mastermind-like protein 1) for binding to RBPJ, thereby impairing the NICD (intracellular domain of the Notch protein)/MAML1/RBPJ complex formation. Our study reveals an essential role of endothelial YY1 in controlling sprouting angiogenesis through directly interacting with RBPJ and forming a YY1-RBPJ nuclear repression complex.


Assuntos
Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Morfogênese/fisiologia , Neovascularização Patológica/metabolismo , Fator de Transcrição YY1/metabolismo , Animais , Proteínas de Transporte/metabolismo , Diferenciação Celular , Células Endoteliais/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos/embriologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neovascularização Fisiológica/genética , Neovascularização Fisiológica/fisiologia , Proteínas Nucleares , Ligação Proteica , Receptores Notch/metabolismo , Vasos Retinianos/metabolismo , Transdução de Sinais , Fatores de Transcrição , Fator de Transcrição YY1/genética
19.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 37(2): 200-204, 2020 Feb 10.
Artigo em Chinês | MEDLINE | ID: mdl-32034755

RESUMO

Many recent studies have proved that ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an important nuclear protein associated with tumorigenesis, which plays a significant role in epigenetic regulation, especially in DNA methylation and histone methylation. For its particular domains, UHRF1 plays a critical role in biological behaviors including cell proliferation, cell cycle, and apoptosis. Overexpression of UHRF1 in various tumors is closely associated with the angiogenesis in tumors. This paper will provide a review of the regulation of UHRF1 in DNA methylation and histone methylation, and discuss the potential epigenetic role of UHRF1 in angiogenesis.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Metilação de DNA , Neovascularização Patológica/genética , Ubiquitina-Proteína Ligases/genética , Epigênese Genética , Humanos , Neoplasias/genética , Neoplasias/patologia
20.
Life Sci ; 248: 117463, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32097663

RESUMO

Breast cancer is one of the well-known malignant tumors among women. In spite of attempts to classifying breast cancer according to its histological and molecular properties, it is almost considered as a dilemma in treatment. Nowadays, public and medical attentions have primary focused on foods with anti-cancer properties to alleviate the cancer problems. Flavonoid components such as Quercetin (Qu) as dietary substances with high attention of ordinary people might provide potential of alternative or complementary medicine in breast cancer. With regard to the wide range of health benefits of Qu, researchers have been generally convinced to bring Qu as natural compounds in cancer therapy. Moreover, the high cost of standard cancer treatments and the failure of most conventional treatments have led the medical community to pursue cost-effective prevention and treatment. As a result, a great deal of concentration is attracted to diet/cancer reciprocal action. Therefore, this review study has aimed to identify what has revealed the critical properties of Qu such as anti-inflammatory, anti-oxidant, and even its effect on proliferation, angiogenesis, or apoptosis that are considered as anti-tumor property to enhance breast cancer treatment.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antineoplásicos Fitogênicos/uso terapêutico , Antioxidantes/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/tratamento farmacológico , Quercetina/uso terapêutico , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos como Assunto , Feminino , Humanos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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