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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.
J Biol Regul Homeost Agents ; 31(1): 41-49, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28337869

RESUMO

The high mobility group box 1 (HMGB1) as a conserved non-histone nuclear protein has been involved in a variety of biological processes of cancer, such as cell proliferation, apoptosis, angiogenesis and metastasis. Despite the increased expression of HMGB1 in many malignant tumors, the functions and molecular mechanisms by which HMGB1 contributes to the formation of hemangioma (HA) remain unclear. In the present study, immunohistochemistry was used to detect the expression levels of HMGB1 in different phases of human HAs. Cell function experiments, including MTT, cell colony formation and flow cytometry analysis were performed to evaluate the effects of HMGB1 knockdown on cell proliferation and apoptosis in HA CRL-2586 EOMA cells. As a consequence, we found that HMGB1 expression was significantly increased in proliferating phase HAs compared with the involuting phase HAs and normal skin tissues (P less than 0.01). Moreover, knockdown of HMGB1 gene in vitro suppressed EOMA cell proliferation and colony formation and induced cell apoptosis and cycle arrest at G0/G1 phase by downregulation of PCNA, CyclinD1, p-AKT and upregulation of p53 and cleaved PARP. Taken together, our findings demonstrate that HMGB1 may be implicated in the formation of HA through upregulation of AKT pathway, and represent a potential therapeutic target for treating HA.


Assuntos
Apoptose/genética , Regulação Neoplásica da Expressão Gênica , Proteína HMGB1/antagonistas & inibidores , Hemangioma/genética , Proteínas Proto-Oncogênicas c-akt/genética , Neoplasias Cutâneas/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Ciclina D1/genética , Ciclina D1/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Proteína HMGB1/genética , Proteína HMGB1/metabolismo , Hemangioma/metabolismo , Hemangioma/patologia , Humanos , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/agonistas , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
3.
Int J Immunopathol Pharmacol ; 28(2): 201-8, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25816398

RESUMO

Oxymatrine (OMT), a natural quinolizidine alkaloid, has been known to have anti-inflammation, anti-anaphylaxis, and chemopreventive effects on various cancer cells. To clarify the underlying role and molecular mechanisms of OMT in human hemangioma (HA), in the present study, we examined the expression of hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) in different phases of human HA. After HA derived endothelial cells (HDEC) were pretreated with different concentrations of OMT, cell proliferation, apoptosis, and cycle distribution were evaluated by MTT assay and flow cytometry analysis, respectively. The effects of OMT on expression of HIF-1a signaling were determined by real-time PCR and western blot assays. Our results showed that, the expression of HIF-1a and VEGF was significantly increased in proliferating phase HA, but decreased in involuting phase HA. Moreover, OMT in vitro inhibited proliferative activities and induced cell apoptosis and cycle arrest in G0/G1 phase in HA cells with decreased expression of HIF-1a, VEGF, Bcl-2, and CyclinD1, and increased expression of p53. Taken together, our findings suggest that, the expression of HIF-1a and VEGF is increased in proliferating phase HA, and OMT suppresses cell proliferation and induces cell apoptosis and cycle arrest in proliferative phase HA through inhibition of the HIF-1a signaling pathway, suggesting OMT may provide a novel therapeutic strategy for the treatment of HA.


Assuntos
Alcaloides/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hemangioma/tratamento farmacológico , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Quinolizinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Hemangioma/metabolismo , Humanos , Fase de Repouso do Ciclo Celular/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Int J Oncol ; 44(1): 276-84, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24220265

RESUMO

Livin, a novel member of the human inhibitors of apoptosis protein family, has been shown to be critical for tumor progression and poor prognosis for several types of malignancies. However, limited reports exist regarding the biological functions of Livin in human gastric cancer (GC). The present study investigated the clinical significance of Livin and caspase-3 (CAS-3) in human GC using immunohistochemistry assay, and explore the potential using RNA interference to knockdown Livin expression, including the subsequent effects on tumor growth and invasion in GC cells in vitro and in vivo. Our results showed that the rate of positive expression of Livin was significantly higher in GC tissues compared to that in adjacent non-cancer tissues (ANCT) (64.1 vs. 30.8%, P<0.001), while CAS-3 was lower in GC tissues than in ANCT (33.3 vs. 66.7%, P=0.001). Livin expression was positively correlated with tumor differentiation and lymph node metastases (P=0.009; P=0.007), while CAS-3 was negatively correlated with them (P=0.036; P=0.002) in patients with GC. Furthermore, knockdown of Livin inhibited cell proliferative activities and invasive potential, and induced cell in situ apoptosis in GC cells, accompanied with decreased expression of p38 MAPK, VEGF and MMP-2 and increased expression of CAS-3. In addition, the tumor volumes in the SGC7901 subcutaneous nude mouse model treated with Lv-shLivin was significantly smaller compared to those of the PBS group (P<0.01). Taken together, our findings indicate that the expression of Livin is increased in human GC and correlates with tumor differentiation and lymph node metastases, while knockdown of Livin inhibits cell growth and invasion through blockade of the MAPK pathway in GC cells, suggesting that Livin may be a potential therapeutic target for the treatment of GC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Caspase 3/genética , Proteínas Inibidoras de Apoptose/genética , Proteínas de Neoplasias/genética , Transdução de Sinais , Neoplasias Gástricas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Idoso , Animais , Apoptose/genética , Caspase 3/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Metástase Linfática/genética , Metástase Linfática/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/patologia
5.
Eur J Histochem ; 58(1): 2263, 2014 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-24704994

RESUMO

Angiogenesis is a process of development and growth of new capillary blood vessels from pre-existing vessels. Angiogenic growth factors play important roles in the development and maintenance of some malignancies, of which vascular endothelial growth factor (VEGF)/VEGFR2 interactions are involved in proliferation, migration, and survival of many cancer cells. The aim of this study was to investigate the function of VEGFR2 in human hemangiomas (HAs). Using immunohistochemistry assay, we examined the expression levels of VEGF, VEGFR2, Ki-67, glucose transporter-1 (Glut-1), phosphorylated protein kinase B (p-AKT) and p-ERK in different phases of human HAs. Positive expression of VEGF, VEGFR2, Ki-67, Glut-1, p-AKT and p-ERK was significantly increased in proliferating phase HAs, while decreased in involuting phase HAs (P=0.001; P=0.003). In contrast, cell apoptotic indexes were decreased in proliferating phase HAs, but increased in involuting phase HAs (P<0.01). Furthermore, we used small hairpin RNA (shRNA)-mediated VEGFR2 knockdown in primary HA-derived endothelial cells (HemECs) to understand  the  role  of  VEGF/VEGFR2 signaling. Knockdown of VEGFR2 by Lv-shVEGFR2 inhibited cell viability and induced apoptosis in primary HemECs companied with decreased expression of p-AKT, p-ERK, p-p38MAPK and Ki-67 and increased expression of caspase-3 (CAS-3). Overexpression of VEGFR2 promoted cell viability and blocked apoptosis in Lv-VEGFR2-transfected HemECs. Taken together, our findings demonstrate that, increased expression of VEGFR2 is involved in the development of primary HemECs possibly through regulation of the AKT and ERK pathways, suggesting that VEGFR2 may be a potential therapeutic target for HAs. 


Assuntos
Apoptose , Proliferação de Células , Células Endoteliais/metabolismo , Hemangioma/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Caspase 3/biossíntese , Caspase 3/genética , Linhagem Celular Tumoral , Células Endoteliais/patologia , MAP Quinases Reguladas por Sinal Extracelular/biossíntese , MAP Quinases Reguladas por Sinal Extracelular/genética , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Silenciamento de Genes , Hemangioma/genética , Hemangioma/patologia , Humanos , Antígeno Ki-67/biossíntese , Antígeno Ki-67/genética , Proteínas Proto-Oncogênicas c-akt/biossíntese , Proteínas Proto-Oncogênicas c-akt/genética , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética
6.
Int J Oncol ; 45(3): 1241-9, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24968760

RESUMO

Insulin-like growth factor-II (IGF-II)/IGF2R signaling plays a pivotal role in cell growth, migration and differentiation in many malignancies. An individual with high IGF-II expression levels has a high risk of developing cancer, but IGF2R is often considered to be a tumor suppressor. To date, little has been reported about the role of IGF-II/IGF2R signaling in hemangiomas (HAs). Thus, uncovering the mechanisms of IGF-II/IGF2R signaling is very important to understanding the development of HAs. In the present study, the expression of IGF-II and IGF2R was investigated in 27 cases of HAs of different phases by immunohistochemistry. Through lentivirus-mediated IGF2R siRNA (Lv-siIGF2R) in HA-derived endothelial cells (HDECs), we observed the effects of IGF2R knockdown on the biological behavior of HA cells. We found that the expression of IGF-II and IGF2R was significantly increased in proliferating phase HAs, but decreased in involuting phase HAs. Furthermore, knockdown of IGF2R in vitro significantly diminished the proliferative activity and induced apoptosis and cycle arrest with decreased expression of PCNA, Ki-67, Bcl-2, Cyclin D1 and E and increased the expression of Bax in the proliferative phase HAs (HDEC and CRL-2586 EOMA cells). In addition, the tumor volumes in a subcutaneous HDEC nude mouse model treated with Lv-siIGF2R were significantly smaller than those of the control group. Taken together, our findings indicate that the expression of IGF-II and IGF2R is increased in proliferating phase HAs, and knockdown of IGF2R suppresses proliferation and induces apoptosis in HA cells in vitro and in vivo, suggesting that IGF2R may represent a novel therapeutic target for the treatment of human HAs.


Assuntos
Apoptose , Técnicas de Silenciamento de Genes/métodos , Hemangioma/terapia , Fator de Crescimento Insulin-Like II/metabolismo , RNA Interferente Pequeno/metabolismo , Receptor IGF Tipo 2/antagonistas & inibidores , Animais , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Terapia Genética , Hemangioma/patologia , Humanos , Técnicas In Vitro , Lentivirus/genética , Camundongos , Camundongos Nus , Neoplasias Experimentais , RNA Interferente Pequeno/genética , Receptor IGF Tipo 2/genética
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