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1.
J Agric Food Chem ; 67(32): 8855-8867, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31343893

RESUMO

Abalone (Haliotis discus hannai) is a precious seafood in the market. It has been reported that biological active substances derived from abalone have anti-oxidative, anti-inflammatory, anti-bacterial, and anti-thrombosis potential. However, there were few studies to assess whether they have anti-cancer potential. In this study, we evaluated the anti-metastasis and anti-pro-angiogenic factors and mechanism of action of boiled abalone byproduct peptide (BABP, EMDEAQDPSEW) in human fibrosarcoma (HT1080) cells and human umbilical vein endothelial cells (HUVECs). The results demonstrated that BABP treatment significantly lowers migration and the invasion of HT1080 cells and HUVECs. BABP inhibits phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase (MMP) expression and activity by blocking mitogen-activated protein kinases (MAPKs) and NF-κB signaling and hypoxia-induced vascular endothelial growth factor (VEGF) secretion and hypoxia inducible factor (HIF)-1α accumulation through suppressing the AKT/mTOR signal pathway. BABP treatment inhibits VEGF-induced VEGFR-2 expression and tube formation in HUVECs. The effect of BABP on anti-metastatic and anti-vascular activity in HT1080 cells and HUVECs revealed that BABP may be a potential pharmacophore for tumor therapy in the future.


Assuntos
Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Gastrópodes/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Peptídeos/farmacologia , Resíduos/análise , Inibidores da Angiogênese/química , Inibidores da Angiogênese/isolamento & purificação , Animais , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/fisiopatologia , Peptídeos/química , Peptídeos/isolamento & purificação , Frutos do Mar/análise , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo
2.
Int J Oncol ; 55(1): 167-178, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31180533

RESUMO

Vascular endothelial growth inhibitor (VEGI; also referred to as TNFSF15 or TL1A) is involved in the modulation of vascular homeostasis. VEGI is known to operate via two receptors: Death receptor­3 (DR3) and decoy receptor­3 (DcR3). DR3, which is thus far the only known functional receptor for VEGI, contains a death domain and induces cell apoptosis. DcR3 is secreted as a soluble protein and antagonizes VEGI/DR3 interaction. Overexpression of DcR3 and downregulation of VEGI have been detected in a number of cancers. The aim of the present study was to investigate the effects of sodium valproate (VPA), a histone deacetylase inhibitor, in combination with hydralazine hydrochloride (Hy), a DNA methylation inhibitor, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Combination treatment with Hy and VPA synergistically induced the expression of VEGI and DR3 in both OS and HMVE cells, without inducing DcR3 secretion. In addition, it was observed that the combination of VPA and Hy significantly enhanced the inhibitory effect on vascular tube formation by VEGI/DR3 autocrine and paracrine pathways. Furthermore, the VEGI/VEGF­A immune complex was pulled down by immunoprecipitation. Taken together, these findings suggest that DNA methyltransferase and histone deacetylase inhibitors not only have the potential to induce the re­expression of tumor suppressor genes in cancer cells, but also exert anti­angiogenic effects, via enhancement of the VEGI/DR3 pathway and VEGI/VEGF­A interference.


Assuntos
Neoplasias Ósseas/tratamento farmacológico , Hidralazina/farmacologia , Osteossarcoma/tratamento farmacológico , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Ácido Valproico/farmacologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Neoplasias Ósseas/irrigação sanguínea , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Sinergismo Farmacológico , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Inibidores Enzimáticos/farmacologia , Epigênese Genética , Humanos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Osteossarcoma/irrigação sanguínea , Osteossarcoma/genética , Osteossarcoma/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Membro 25 de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 25 de Receptores de Fatores de Necrose Tumoral/genética , Transcrição Genética/efeitos dos fármacos , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética
3.
Anticancer Res ; 39(5): 2277-2287, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092419

RESUMO

BACKGROUND: Low success rates in oncology drug development are prompting re-evaluation of preclinical models, including orthotopic tumor engraftment. In breast cancer models, tumor cells are typically injected into mouse mammary fat pads (MFP). However, this approach bypasses the epithelial microenvironment, potentially altering tumor properties in ways that affect translational application. MATERIALS AND METHODS: Tumors were generated by mammary intraductal (MIND) engraftment of 4T1 carcinoma cells. Growth, histopathology, and molecular features were quantified. RESULTS: Despite growth similar to that of 4T1 MFP tumors, 4T1 MIND tumors exhibit distinct histopathology and increased metastasis. Furthermore, >6,000 transcripts were found to be uniquely up-regulated in 4T1 MIND tumor cells, including genes that drive several cancer hallmarks, in addition to two known therapeutic targets that were not up-regulated in 4T1 MFP tumor cells. CONCLUSION: Engraftment into the epithelial microenvironment generates tumors that more closely recapitulate the complexity of malignancy, suggesting that intraductal adaptation of orthotopic mammary models may be an important step towards improving outcomes in preclinical drug screening and development.


Assuntos
Neoplasias da Mama/genética , Neoplasias Mamárias Animais/genética , Proteínas de Neoplasias/genética , Neovascularização Patológica/genética , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Mamárias Animais/tratamento farmacológico , Neoplasias Mamárias Animais/patologia , Camundongos , Terapia de Alvo Molecular , Metástase Neoplásica , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Microambiente Tumoral/genética
4.
Anticancer Res ; 39(5): 2317-2324, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092423

RESUMO

BACKGROUND/AIM: Thrombospondins (TSPs) play a role as inhibitors of angiogenesis under various pathological conditions. The aim of the study was to evaluate the pathological significance and prognostic role of the 4N1K-peptide (KRFYVVMWKK), which is derived from TSP-1 and -2, in bladder cancer. MATERIALS AND METHODS: Two-hundred and six bladder cancer tissues were examined for expression of TSP-1, TSP-2, and 4N1K-peptide by immunohistochemistry. Cancer cell proliferation, apoptosis, angiogenesis and matrix metalloproteinase (MMP)-9 immunoreactivity were also examined. RESULTS: Expression of TSP-2 and 4N1K-peptide was negatively associated with T stage, metastasis, and grade. TSP-2 expression was negatively associated with cancer cell proliferation and MMP-9 expression, whereas 4N1K-peptide was significantly associated with apoptosis, angiogenesis, and MMP-9 expression. Multivariate analysis showed that 4N1K-peptide expression was a significant predictor of metastasis (hazard ratio=3.90, p=0.002). CONCLUSION: TSP-2 and 4N1K peptide played important roles in malignant aggressiveness and progression of bladder cancer via complex mechanisms involving cell proliferation, apoptosis, angiogenesis, and MMP-9.


Assuntos
Metaloproteinase 9 da Matriz/genética , Neovascularização Patológica/genética , Trombospondina 1/genética , Trombospondinas/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose , Biomarcadores Tumorais/genética , Proliferação de Células , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neovascularização Patológica/patologia , Oligopeptídeos/genética , Prognóstico , Neoplasias da Bexiga Urinária/patologia
5.
Anticancer Res ; 39(5): 2341-2350, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31092426

RESUMO

BACKGROUND/AIM: Chitinase 3 like 1 (CHI3L1) is a secretion glycoprotein. Elevated levels of this protein are observed in cancer diseases. The biological role of CHI3L1 is not yet fully known, but the connection between CHI3L1 and angiogenesis has been shown. Recent reports also describe the association of Nogo isoforms and Nogo-B receptor (NgBR) with a proliferative potential, cancer cell invasiveness, and angiogenesis. The aim of this study was to evaluate the levels of CHI3L1, Nogo-A, Nogo-A/B, and NgBR and correlate them with clinical-pathological data, to study their role in angiogenesis in invasive ductal breast carcinoma (IDC). MATERIALS AND METHODS: A total of 77 IDC cases were used in the study. Immunohistochemistry was used to determine the level of expression of CHI3L1, Nogo-A, Nogo-A/B, NgBR and vascular endothelial growth factors (VEGFA, VEGFC and VEGFD). The obtained results were subjected to statistical analysis including clinicalpathological data. RESULTS: A statistically significant positive correlation of CHI3L1 and Nogo-A expression (r=0.474, p>0.0001) and a positive correlation of Nogo-A and VEGFC expression (r=0.280, p=0.013) were found. CONCLUSION: CHI3L1 and Nogo-A are important in angiogenesis in IDC.


Assuntos
Carcinoma Ductal de Mama/genética , Proteína 1 Semelhante à Quitinase-3/genética , Neovascularização Patológica/genética , Proteínas Nogo/genética , Fator C de Crescimento do Endotélio Vascular/genética , Idoso , Carcinoma Ductal de Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Receptores de Superfície Celular/genética , Fator A de Crescimento do Endotélio Vascular/genética , Fator D de Crescimento do Endotélio Vascular/genética
6.
Cell Physiol Biochem ; 52(6): 1569-1583, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31145841

RESUMO

BACKGROUND/AIMS: Shear stress plays major roles in developmental angiogenesis, particularly in blood vessel remodeling and maturation but little is known about the shear stress sensors involved in this process. Our recent study identified endothelial Kir2.1 channels as major contributors to flow-induced vasodilation, a hallmark of the endothelial flow response. The goal of this study is to establish the role of Kir2.1 in the regulation of retinal angiogenesis. METHODS: The retina of newly born Kir2.1+/- mice were used to investigate the sprouting angiogenesis and remodeling of newly formed branched vessels. The structure, blood density and mural cell coverage have been evaluated by immunohistochemistry of the whole-mount retina. Endothelial cell alignment was assessed using CD31 staining. The experiments with flow-induced vasodilation were used to study the cerebrovascular response to flow. RESULTS: Using Kir2.1-deficient mice, we show that the retinas of Kir2.1+/- mice have higher vessel density, increased lengths and increased number of the branching points, as compared to WT littermates. In contrast, the coverage by αSMA is decreased in Kir2.1+/- mice while pericyte coverage does not change. Furthermore, to determine whether deficiency of Kir2.1 affects vessel pruning, we discriminated between intact and degraded vessels or "empty matrix sleeves" and found a significant reduction in the number of empty sleeves on the peripheral part of the retina or "angiogenic front" in Kir2.1+/- mice. We also show that Kir2.1 deficiency results in decreased endothelial alignment in retinal endothelium and impaired flow-induced vasodilation of cerebral arteries, verifying the involvement of Kir2.1 in shear-stress sensing in retina and cerebral circulation. CONCLUSION: This study shows that shear-stress sensitive Kir2.1 channels play an important role in pruning of excess vessels and vascular remodeling during retinal angiogenesis. We propose that Kir2.1 mediates the effect of shear stress on vessel maturation.


Assuntos
Neovascularização Patológica/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Estresse Mecânico , Animais , Artérias Cerebrais/metabolismo , Artérias Cerebrais/patologia , Células Endoteliais/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Mutantes , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Canais de Potássio Corretores do Fluxo de Internalização/genética , Retina/metabolismo , Retina/patologia
7.
Int J Mol Sci ; 20(9)2019 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035644

RESUMO

Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.


Assuntos
Linfangiogênese , Mastócitos/imunologia , Neovascularização Patológica , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia , Animais , Biomarcadores , Regulação Neoplásica da Expressão Gênica , Humanos , Linfangiogênese/genética , Linfangiogênese/imunologia , Mastócitos/metabolismo , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Transdução de Sinais , Neoplasias Gástricas/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
J Mol Histol ; 50(3): 239-251, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31049798

RESUMO

Reduced expression of endothelial nitric oxide synthase (eNOS) is a hallmark of endothelial dysfunction in diabetes, which predisposes diabetic patients to numerous cardiovascular complications including blunted angiogenesis. The Krüppel-like factor (KLF) five has been implicated as a central regulator of cardiovascular remodeling, but its role in endothelial cells (ECs) remains poorly understood. We show here that expression of endothelial KLF5 was significantly increased in the ECs from mouse diabetes mellitus type 2 (T2DM) model, when compared to non-diabetic or T1DM mouse. KLF5 up-regulation by insulin was dependent on activation of multiple pathways, including mammalian target of rapamycin, oxidative stress and Protein kinase C pathways. Hyperinsulinemia-induced KLF5 inhibited endothelial function and migration, and thereby compromised in vitro and in vivo angiogenesis. Mechanistically, KLF5 acted in concert with the MTA1 coregulator to negatively regulate NOS3 transcription, thereby leading to the diminished eNOS levels in ECs. Conversely, potentiation of cGMP content (the essential downstream effector of eNOS signaling) by pharmacological approaches successfully rescued the endothelial proliferation and in vitro tube formation, in the HUVECs overexpressing the exogenous KLF5. Collectively, the available data suggest that the augmentation of endothelial KLF5 expression by hyperinsulinemia may represent a novel mechanism for negatively regulating eNOS expression, and may thus help to explain for the T2DM-related endothelial dysfunction at the transcriptional level.


Assuntos
Hiperinsulinismo/genética , Fatores de Transcrição Kruppel-Like/genética , Neovascularização Patológica/genética , Óxido Nítrico Sintase Tipo III/genética , Animais , Movimento Celular/genética , Proliferação de Células/genética , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Hiperinsulinismo/patologia , Masculino , Camundongos , Estresse Oxidativo/genética , Proteína Quinase C/genética , Transdução de Sinais/genética
9.
J Cancer Res Ther ; 15(2): 329-335, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30964106

RESUMO

Aim: The aim of this study was to investigate the effect of microRNA-1224-5p (miR-1224-5p) on tumor endothelial cells (TECs) of human hepatocellular carcinoma (HCC). Subjects and Methods: Oligonucleotides were chemically synthesized and transfected into TECs using Lipofectamine 2000. TECs were divided into three groups, namely a control (CON) group without transfection, a negative control (NC) group transfected with negative control oligonucleotides and green fluorescent protein (GFP), and a micro-up (MU) group transfected with miR-1224-5p mimic and GFP. The expression of miR-1224-5p was quantified via quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The proliferation of TECs was detected using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the optical density value at 490 nm was measured after every 24 h. Apoptosis was detected via flow cytometry using a 7-aminoactinomycin/APC Annexin V kit. The migration and invasion of TECs were detected using transwell assay. The tube formation ability was evaluated using the tube formation assay. Results: Oligonucleotides were successfully transduced into TECs, and the expression of miR-1224-5p was specifically upregulated. The results of qRT-PCR analysis showed that the expression of miR-1224-5p was significantly upregulated in the MU group (2-ΔΔCt = 3.27 ± 0.15) than in the CON group (2-ΔΔCt = 1) and NC group (2-ΔΔCt = 1.08 ± 0.11) (P < 0.01). The results of MTT assay showed that the cell proliferation was significantly inhibited in the MU group at four time points than in the CON and NC groups (P < 0.01). Flow cytometry analysis revealed the significant increase in apoptosis of cells from the MU group (19.29% ± 0.95%) than those from the CON (8.73% ± 0.64%) and NC (9.51% ± 0.56%) (P < 0.01) groups. The migration ability was significantly inhibited in MU group (51.0 ± 3.6) as compared with CON (77.7 ± 2.5) and NC (79.2 ± 3.5) groups (P < 0.01). The invasion ability of TECs was significantly inhibited in MU group (9.8 ± 1.3) than in CON (15.8 ± 0.8) and NC (15.4 ± 0.9) groups (P < 0.01). The ability of tube formation of TECs was completely inhibited in MU group but remained unaffected in CON and NC groups. Conclusions: miR-1224-5p may serve as a potential tumor suppressor in HCC. Upregulation in miR-1224-5p expression may decrease proliferation, induce apoptosis, inhibit migration and invasion, and suppress tube formation in TECs of human HCC.


Assuntos
Carcinoma Hepatocelular/genética , Células Endoteliais/metabolismo , Neoplasias Hepáticas/genética , MicroRNAs/genética , Apoptose , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Citometria de Fluxo , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Neoplasias Hepáticas/patologia , Neovascularização Patológica/genética , Transfecção
10.
J Exp Clin Cancer Res ; 38(1): 174, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023336

RESUMO

BACKGROUND: Non-small cell lung cancer (NSCLC) is a devastating disease with a heterogeneous prognosis, and the molecular mechanisms underlying tumor progression remain elusive. Mammalian Eps15 homology domain 1 (EHD1) plays a promotive role in tumor progression, but its role in cancer angiogenesis remains unknown. This study thus explored the role of EHD1 in angiogenesis in NSCLC. METHODS: The changes in angiogenesis were evaluated through human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation assays. The impact of EHD1 on ß2-adrenoceptor (ß2AR) signaling was evaluated by Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) analysis, and enzyme-linked immunosorbent assay (ELISA). The interaction between EHD1 and ß2AR was confirmed by immunofluorescence (IF) and coimmunoprecipitation (Co-IP) experiments, and confocal microscopy immunofluorescence studies revealed that ß2AR colocalized with the recycling endosome marker Rab11, which indicated ß2AR endocytosis. Xenograft tumor models were used to investigate the role of EHD1 in NSCLC tumor growth. RESULTS: The microarray analysis revealed that EHD1 was significantly correlated with tumor angiogenesis, and loss- and gain-of-function experiments demonstrated that EHD1 potentiates HUVEC proliferation, migration and tube formation. EHD1 knockdown inhibited ß2AR signaling activity, and EHD1 upregulation promoted vascular endothelial growth factor A (VEGFA) and ß2AR expression. Interestingly, EHD1 interacted with ß2AR and played a novel and critical role in ß2AR endocytic recycling to prevent receptor degradation. Aberrant VEGFA or ß2AR expression significantly affected EHD1-mediated tumor angiogenesis. The proangiogenic role of EHD1 was confirmed in xenograft tumor models, and immunohistochemistry (IHC) analysis confirmed that EHD1 expression was positively correlated with VEGFA expression, microvessel density (MVD) and ß2AR expression in patient specimens. CONCLUSION: Collectively, the data obtained in this study suggest that EHD1 plays a critical role in NSCLC angiogenesis via ß2AR signaling and highlight a potential target for antiangiogenic therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Neovascularização Patológica/genética , Receptores Adrenérgicos beta 2/genética , Fator A de Crescimento do Endotélio Vascular/genética , Proteínas de Transporte Vesicular/genética , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Movimento Celular/genética , Proliferação de Células/genética , Endocitose/genética , Ensaio de Imunoadsorção Enzimática , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Microscopia Confocal , Neovascularização Patológica/patologia , Prognóstico , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rab de Ligação ao GTP/genética
11.
J Exp Clin Cancer Res ; 38(1): 173, 2019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023337

RESUMO

BACKGROUND: Breast cancer angiogenesis is key for metastasis and predicts a poor prognosis. Angiotensin-converting enzyme 2 (ACE2), as a member of the renin-angiotensin system (RAS), was reported to restrain the progression of hepatocellular carcinoma (HCC) and non-small cell lung cancer (NSCLC) through inhibiting angiogenesis. However, the relationship between ACE2 and breast cancer angiogenesis remains unclear. METHODS: The prognosis and relative gene selection were analysed using the GEPIA, GEO, TCGA and STRING databases. ACE2 expression in breast cancer tissue was estimated by reverse transcription-quantitative polymerase chain reaction (qPCR). Breast cancer cell migration, proliferation and angiogenesis were assessed by Transwell migration, proliferation, tube formation, and wound healing assays. The expression of vascular endothelial growth factor A (VEGFa) was detected by qPCR and Western blotting. The phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2), mitogen-activated protein kinase 1/2 (MEK1/2), and extracellular signal-regulated protein kinase 1/2 (ERK1/2) was examined by Western blotting. Breast cancer metastasis and angiogenesis in vivo were measured using a zebrafish model. RESULTS: ACE2 was downregulated in breast cancer patients. Patients with higher ACE2 expression had longer relapse-free survival (RFS). In vitro, ACE2 inhibited breast cancer migration. Meanwhile, ACE2 in breast cancer cells inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, tube formation and migration. In the zebrafish model, ACE2 inhibited breast cancer cell metastasis, as demonstrated by analyses of the number of disseminated foci and the metastatic distance. Neo-angiogenesis was also decreased by ACE2. ACE2 downregulated the expression of VEGFa in breast cancer cells. Furthermore, ACE2 in breast cancer cells inactivated the phosphorylation of VEGFR2, MEK1/2, and ERK1/2 in HUVECs. CONCLUSIONS: Our findings suggest that ACE2, as a potential resister to breast cancer, might inhibit breast cancer angiogenesis through the VEGFa/VEGFR2/ERK pathway. TRIAL REGISTRATION: Retrospectively registered.


Assuntos
Neoplasias da Mama/genética , Neovascularização Patológica/genética , Peptidil Dipeptidase A/genética , Fator A de Crescimento do Endotélio Vascular/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Animais , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/patologia , Movimento Celular/genética , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases/genética , Células MCF-7 , Metástase Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Fosforilação , Peixe-Zebra
12.
Oncol Rep ; 41(6): 3508-3516, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31002348

RESUMO

Gemcitabine (Gem) is widely used as chemotherapy for pancreatic cancer (PaCa), but its effect is not fully satisfactory. One of the reasons for this is the acquisition of Gem resistance (Gem­R). To elucidate the mechanism of Gem­R, two Gem­R PaCa cell lines were established from AsPC­1 and MIA PaCa­2 cells. It was demonstrated that expression of interleukin­8 (IL­8) mRNA was significantly upregulated in Gem­R PaCa cells by cDNA microarray and RT­qPCR analyses. Increased IL­8 secretion by Gem­R cells was confirmed by cytokine array and enzyme­linked immunosorbent assay. Moreover, we found that co­culture with Gem­R PaCa cells significantly enhanced tube formation of human umbilical vein endothelial cells, and treatment with an anti­CXCR2 (main receptor for IL­8) antibody significantly prevented this effect. We previously reported that a chemokine network centered on the IL­8/CXCR2 axis plays an important role in PaCa angiogenesis, and suppression of this axis has an antitumor effect. Since acquisition of Gem­R increased IL­8 production and consequently increased tumor angiogenesis, the IL­8/CXCR2 axis may be a potential novel therapeutic target for PaCa after acquiring Gem­R.


Assuntos
Desoxicitidina/análogos & derivados , Interleucina-8/genética , Neovascularização Patológica/genética , Neoplasias Pancreáticas/tratamento farmacológico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Neovascularização Patológica/induzido quimicamente , Neovascularização Patológica/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia
13.
Mol Cancer ; 18(1): 83, 2019 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954079

RESUMO

The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo" (proteins, lipids, or nucleic acids) that can redirect the function of a recipient cell. Currently, the molecular mechanisms and clinical applications of EVs in head and neck cancers (HNCs) are still at an early stage and need to be further investigate. In this review, we provide insight into the TME of HNCs, classifying and summarizing EVs derived from different cell types and illuminating their complex signaling networks involved in mediating tumor proliferation, invasion and metastasis, vascular angiogenesis and cancer drug resistance. In addition, we highlight the application of EVs in HNCs, underlining the special pathological and physiological environment of HNCs. The application of tumor heterogeneous EVs in saliva and circulating blood diagnostics will provide a new perspective for the early screening, real-time monitoring and prognostic risk assessment of HNCs. Given the concept of precise and individual therapy, nanostructured EVs are equipped with superior characteristics of biocompatibility, low immunogenicity, loadability and modification ability, making these molecules one of the new strategies for HNCs treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Vesículas Extracelulares/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Células Neoplásicas Circulantes/metabolismo , Neovascularização Patológica/metabolismo , Antineoplásicos/uso terapêutico , Transporte Biológico , Biomarcadores Tumorais/genética , Comunicação Celular , Resistencia a Medicamentos Antineoplásicos/genética , Vesículas Extracelulares/química , Vesículas Extracelulares/classificação , Vesículas Extracelulares/genética , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Metástase Linfática , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Células Neoplásicas Circulantes/efeitos dos fármacos , Células Neoplásicas Circulantes/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
14.
Mol Cancer ; 18(1): 88, 2019 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-30979371

RESUMO

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) and cancer stem cells (CSCs) are two important cellular components in the tumor microenvironment, which may modify the cancer phenotype and affect patient survival. However, the crosstalk between MDSCs and multiple myeloma stem cells (MMSCs) are relatively poorly understood. METHODS: The frequencies of granulocytic-MDSCs (G-MDSCs) in MM patients were detected by flow cytometry and their association with the disease stage and patient survival were analyzed. RT-PCR, flow cytometry, western blot and sphere formation assays were performed to investigate the effects of G-MDSCs, piRNA-823 and DNA methylation on the maintenance of stemness in MM. Then a subcutaneous tumor mouse model was constructed to analyze tumor growth and angiogenesis after G-MDSCs induction and/or piRNA-823 knockdown in MM cells. RESULTS: Our clinical dataset validated the association between high G-MDSCs levels and poor overall survival in MM patients. In addition, for the first time we showed that G-MDSCs enhanced the side population, sphere formation and expression of CSCs core genes in MM cells. Moreover, the mechanism study showed that G-MDSCs triggered piRNA-823 expression, which then promoted DNA methylation and increased the tumorigenic potential of MM cells. Furthermore, silencing of piRNA-823 in MM cells reduced the stemness of MMSCs maintained by G-MDSCs, resulting in decreased tumor burden and angiogenesis in vivo. CONCLUSION: Altogether, these data established a cellular, molecular, and clinical network among G-MDSCs, piRNA-823, DNA methylation and CSCs core genes, suggesting a new anti-cancer strategy targeting both G-MDSCs and CSCs in MM microenvironment.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/genética , Células Supressoras Mieloides/metabolismo , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/metabolismo , RNA Interferente Pequeno/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Comunicação Celular , Linhagem Celular Tumoral , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Feminino , Granulócitos/metabolismo , Granulócitos/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Células Supressoras Mieloides/patologia , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Neovascularização Patológica/mortalidade , Neovascularização Patológica/patologia , RNA Interferente Pequeno/antagonistas & inibidores , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Análise de Sobrevida , Microambiente Tumoral/genética , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Int J Mol Med ; 43(6): 2387-2397, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31017266

RESUMO

The most common and aggressive type of brain cancer in adults is glioblastoma multiforme (GBM), and hypoxia is a common feature of glioblastoma. As the histological features of glioma include capillary endothelial cell proliferation, they are highly prone to invading the surrounding normal brain tissue, which is often one of the reasons for the failure of treatment. However, the mechanisms involved in this process are not fully understood. MicroRNAs (miRs) are a class of non­coding RNA that are able to inhibit the malignant progression of tumor cells through the regulation of downstream genes. In the present study, the low expression of miR­576­3p was detected in glioma samples and hypoxia­treated glioma cells using a reverse transcription­quantitative polymerase chain reaction. The present study focused on the effects of miR­576­3p on hypoxia­induced glioma. The results of the functional experiments revealed that the overexpression of miR­576­3p significantly inhibited the migration and pro­angiogenic abilities of the glioma cells under hypoxic conditions (P<0.05) compared with in the lentivirus­miR­negative control group. Furthermore, luciferase reporter gene assays were used to validate the hypothesis that miR­576­3p interacts with the 3'­untranslated region of hypoxia­inducible factor­1α (HIF­1α) and induces a reduction in the protein levels of matrix metalloproteinase­2 and vascular endothelial growth factor. Rescue experiments demonstrated that the restoration of HIF­1α expression attenuated the effect of miR­576­3p on the migration and proangiogenic abilities of glioma cells. In conclusion, the present study confirms that miR­576­3p is a novel GBM inhibitor and its inhibition of the migration and proangiogenic capacity of hypoxia­induced glioma cells is mediated by HIF­1α.


Assuntos
Neoplasias Encefálicas/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Glioblastoma/patologia , Humanos , Neovascularização Patológica/patologia , Hipóxia Tumoral
16.
Int J Mol Sci ; 20(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027366

RESUMO

Alternative splicing of pre-mRNA allows the generation of multiple splice isoforms from a given gene, which can have distinct functions. In fact, splice isoforms can have opposing functions and there are many instances whereby a splice isoform acts as an inhibitor of canonical isoform function, thereby adding an additional layer of regulation to important processes. Angiogenesis is an important process that is governed by alternative splicing mechanisms. This review focuses on the alternative spliced isoforms of key genes that are involved in the angiogenesis process; VEGF-A, VEGFR1, VEGFR2, NRP-1, FGFRs, Vasohibin-1, Vasohibin-2, HIF-1α, Angiopoietin-1 and Angiopoietin-2.


Assuntos
Processamento Alternativo/fisiologia , Neovascularização Patológica/metabolismo , Processamento Alternativo/genética , Angiopoietinas/genética , Angiopoietinas/metabolismo , Animais , Humanos , Neovascularização Patológica/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo
17.
Tumour Biol ; 42(4): 1010428319835684, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30957671

RESUMO

We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical-pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27-0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Antígeno Ki-67/genética , Neovascularização Patológica/genética , Adulto , Idoso , Apoptose/genética , Proliferação de Células/genética , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Endoglina/genética , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/epidemiologia , Neovascularização Patológica/patologia , Prognóstico
18.
Tumour Biol ; 42(4): 1010428319842699, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30967059

RESUMO

OBJECTIVES: Adiponectin is a cytokine secreted from adipose tissue that regulates energy homeostasis, inflammation, and cell proliferation. Obesity is associated with increased risk of various cancers, including ovarian cancer. Adipokines, including adiponectin, have been implicated as a factor linking obesity and carcinogenesis. The oncogenic role of adiponectin is not known with regard to various cancer types. We sought to determine the role of adiponectin in angiogenesis in ovarian cancer in vitro. METHODS: We transfected SKOV3 cells with vascular endothelial growth factor small interfering RNA in order to identify the independent angiogenic role of adiponectin in ovarian cancer. The vascular endothelial growth factor knockdown SKOV3 cell lines were treated with adiponectin for 48 h. The cytokines involved in adiponectin-mediated angiogenesis were explored using the human angiogenesis cytokine array and were verified with the enzyme-linked immunosorbent assay. The angiogenic effect of adiponectin was evaluated using the human umbilical vein endothelial cell tube formation assay. We also investigated the effects of adiponectin treatment on the migration and invasion of SKOV3 cells. RESULTS: The number of tubes formed by human umbilical vein endothelial cell decreased significantly after knockdown of vascular endothelial growth factor (via transfection of vascular endothelial growth factor small interfering RNA into SKOV3 cells). When these vascular endothelial growth factor knockdown SKOV3 cells were treated with adiponectin, there was an increase in the number of tubes in a tube formation assay. Following adiponectin treatment, the CXC chemokine ligand 1 secretion increased in a cytokine array. This was confirmed by both enzyme-linked immunosorbent assay and Western blot. The increased secretion of CXC chemokine ligand 1 by adiponectin occurred regardless of vascular endothelial growth factor knockdown. In addition, the induction of migration and invasion of SKOV3 cells were significantly stronger with adiponectin treatment than they were without. CONCLUSION: Adiponectin treatment of ovarian cancer cells induces angiogenesis via CXC chemokine ligand 1 independently of vascular endothelial growth factor. These findings suggest that adiponectin may serve as a novel therapeutic target for ovarian cancer.


Assuntos
Adiponectina/genética , Quimiocina CXCL1/genética , Neovascularização Patológica/genética , Neoplasias Ovarianas/genética , Adiponectina/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Invasividade Neoplásica/genética , Neovascularização Patológica/complicações , Neovascularização Patológica/patologia , Neoplasias Ovarianas/complicações , Neoplasias Ovarianas/patologia , RNA Interferente Pequeno/genética , Fator A de Crescimento do Endotélio Vascular/genética
19.
Int J Mol Sci ; 20(7)2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-30935090

RESUMO

BACKGROUND: In pregnancy, excessive inflammation and break down of immunologic tolerance can contribute to miscarriage. Endothelial cells (ECs) are able to orchestrate the inflammatory processes by secreting pro-inflammatory mediators and bactericidal factors by modulating leakiness and leukocyte trafficking, via the expression of adhesion molecules and chemokines. The aim of this study was to analyse the differences in the phenotype between microvascular ECs isolated from decidua (DECs) and ECs isolated from human skin (ADMECs). METHODS: DECs and ADMECs were characterized for their basal expression of angiogenic factors and adhesion molecules. A range of immunological responses was evaluated, such as vessel leakage, reactive oxygen species (ROS) production in response to TNF-α stimulation, adhesion molecules expression and leukocyte migration in response to TNF-α and IFN-γ stimulation. RESULTS: DECs produced higher levels of HGF, VEGF-A and IGFBP3 compared to ADMECs. DECs expressed adhesion molecules, ICAM-2 and ICAM-3, and a mild response to TNF-α was observed. Finally, DECs produced high levels of CXCL9/MIG and CXCL10/IP-10 in response to IFN-γ and selectively recruited Treg lymphocytes. CONCLUSION: DEC phenotype differs considerably from that of ADMECs, suggesting that DECs may play an active role in the control of immune response and angiogenesis at the foetal-maternal interface.


Assuntos
Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Pele/imunologia , Pele/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Decídua , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Feminino , Imunofluorescência , Humanos , Técnicas In Vitro , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Molécula 3 de Adesão Intercelular/genética , Molécula 3 de Adesão Intercelular/metabolismo , Interferon gama/farmacologia , Neovascularização Patológica/metabolismo , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/efeitos dos fármacos , Fator de Necrose Tumoral alfa/farmacologia
20.
Gene ; 705: 167-176, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31026569

RESUMO

Hemorrhoid is a common and recurrent proctological disease, which is often accompanied by angiogenesis and edema. MicroRNAs in the DLK1-DIO3 imprinted clusters are involved in the development and pathogenesis of mammalian hemorrhoids. Results of the present study indicated multiple, differential expression of DLK1-DIO3 imprinted cluster microRNA between hemorrhoid and normal tissues, where miR-412-5p expression in hemorrhoid tissue was significantly decreased. Fluorescein reporter assays showed that miR-412-5p silenced Xpo1 mRNA expression by targeting its 3'-UTR. Overexpression of miR-412-5p in human umbilical vein endothelial cells (HUVECs) indicated that proliferation, migration and formation of vascular structures in HUVECs were inhibited in vitro. In addition, overexpression of miR-412-5p significantly inhibited Xpo1 expression and promoted upregulation of the p53 protein and its retention in the nucleus. Simultaneously, expression of p66SHC and p16 proteins was activated. In summary, downregulation of endogenous miR-412-5p expression in hemorrhoid vascular endothelial cells leads to high expression of the target gene Xpo1 and translocation of the p53 protein out of the nucleus, rendering it unable to activate p66SHC and p16. This ultimately weakens regulation of the vascular endothelial cell cycle, thereby accelerating the division of hemorrhoid vascular endothelial cells, leading to angiogenesis.


Assuntos
Hemorroidas/genética , Carioferinas/genética , MicroRNAs/genética , Neovascularização Patológica/genética , Receptores Citoplasmáticos e Nucleares/genética , Regiões 3' não Traduzidas , Adulto , Movimento Celular , Núcleo Celular/metabolismo , Proliferação de Células , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Regulação para Baixo , Feminino , Regulação da Expressão Gênica , Impressão Genômica , Hemorroidas/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/metabolismo , Transdução de Sinais , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src/metabolismo , Proteína Supressora de Tumor p53/metabolismo
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