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1.
Eur J Pharmacol ; 889: 173493, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-32860808

RESUMO

Gastric cancer (GC) is one of the most common malignant neoplasms of the digestive system, with China leading in terms of morbidity and mortality rates. Betulinic acid (BA) is a widely-occurring pentacyclic triterpenoid that has been reported to exhibit potent anti-inflammatory, antioxidant, and antitumor activities. BA can combat tumors by inducing apoptosis, regulating cell cycle, and inhibiting autophagy, but its mechanism of action in the context of GC is unclear. A preliminary study found that higher expression of vasodilator-stimulated phosphoprotein (VASP) was correlated with migration in the GC cell line. In this study, BGC-823 cells and MNK45 cells were treated with BA for investigating its effect on the proliferation and migration of cells. Moreover, the expression of VASP and upstream signal molecules were also investigated in this background. The results showed BA could inhibit the proliferation and migration the GC cells. Furthermore, NF-κB acted as a transcription factor to upregulate VASP expression. Moreover, BA could downregulate the expression of VASP at the protein and mRNA level by inhibiting NF-κB activity. In conclusion, these results suggest that BA could inhibit the expression of VASP by negatively regulating NF-κB, thereby inhibiting the proliferation and migration of the GC cells. Our study provides a theoretical basis for exploring the molecular mechanism underlying BA-induced inhibition of proliferation and migration in GC cells.

2.
Int J Biol Sci ; 15(12): 2733-2749, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754343

RESUMO

Breast cancer is one of the most common malignant tumors worldwide. Metastasis remains the leading cause of death in breast cancer patients. Research on the mechanism of breast cancer metastasis has become a core issue in breast cancer research. Our previous series of studies have shown that VASP, as a key oncogene, plays an important role in the development of various tumors such as breast cancer. In this study, we find that miR-638 can target to inhibit VASP expression, and Lin28 acts as an RNA-binding protein to regulate the processing of miR-638, which inhibits its maturation and promotes the expression of VASP. In addition, we also find that CREB1 acts as a transcription factor that binds to the promoter of Lin28 gene and activates the Lin28/miR-638/VASP pathway. Furthermore, CREB1 can also directly bind to the promoter of VASP, and activate VASP expression, forming a CREB/Lin28/miR-638/VASP interactive network, which plays an important role in promoting cell proliferation and migration in breast cancer. Our study explained the mechanism of CREB1/Lin28/miR-638/VASP network promoting the development of breast cancer, which further elucidated the mechanism of VASP as a key oncogene, and also provided a theoretical basis for expanding new approaches to tumor biotherapy.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Animais , Biomarcadores Tumorais , Neoplasias da Mama/genética , Moléculas de Adesão Celular/genética , Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Fator de Crescimento Epidérmico/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Camundongos , Camundongos Nus , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Neoplasias Experimentais , Fosfoproteínas/genética , Prognóstico , Mapas de Interação de Proteínas , Proteínas de Ligação a RNA/genética , Cicatrização
3.
Pathol Res Pract ; 215(10): 152575, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31387807

RESUMO

The important role of LncRNA in the development of breast cancer is attracting more and more attention. In the previous study, we found that the expression level of LncRNA SNHG6 in breast cancer tissues and cells was significantly increased, but its mechanism in the development of breast cancer was still unclear. Our study found that knockdown of SNHG6 significantly inhibited the proliferation, migration and invasion of breast cancer cells MCF-7 and MDA-MB-231 cells. Further study showed that knockdown of SNHG6 significantly inhibited the expression level of VASP. More importantly, SNHG6 and VASP both can bind directly to miR-26a, suggesting that SNHG6 could act as a ceRNA to sponge miR-26a, thereby promoting the expression of VASP, which leading to activated proliferation, migration and invasion of breast cancer cells. Taken together, this study revealed the important role of the SNHG6/miR-26a/VASP regulatory network in the development of breast cancer, and provided a reference for exploring new pathogenesis and biomarkers of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Moléculas de Adesão Celular/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Invasividade Neoplásica/genética , Fosfoproteínas/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Inativação Gênica , Humanos , Invasividade Neoplásica/patologia , RNA Longo não Codificante/genética
4.
Cancer Med ; 8(4): 1679-1693, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30806044

RESUMO

Breast cancer is one of the most common malignant tumors among women worldwide. About 70-75% of primary breast cancers belong to estrogen receptor (ER)-positive breast cancer. In the development of ER-positive breast cancer, abnormal activation of the ERα pathway plays an important role and is also a key point leading to the failure of clinical endocrine therapy. In this study, we found that the small molecule peptide chlorotoxin (CTX) can significantly inhibit the proliferation, migration and invasion of breast cancer cells. In in vitro study, CTX inhibits the expression of ERα in breast cancer cells. Further studies showed that CTX can directly bind to ERα and change the protein secondary structure of its LBD domain, thereby inhibiting the ERα signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ERα signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ERα/VASP signaling pathway. In in vivo study, CTX significantly inhibits growth of ER overexpressing breast tumor and, more importantly, based on the mechanism of CTX interacting with ERα, we found that CTX can target ER overexpressing breast tumors in vivo. Our study reveals a new mechanism of CTX anti-ER-positive breast cancer, which also provides an important reference for the study of CTX anti-ER-related tumors.


Assuntos
Moléculas de Adesão Celular/metabolismo , Receptor alfa de Estrogênio/metabolismo , Proteínas dos Microfilamentos/metabolismo , Fosfoproteínas/metabolismo , Venenos de Escorpião/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/genética , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Charibdotoxina/química , Charibdotoxina/isolamento & purificação , Charibdotoxina/farmacologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Proteínas dos Microfilamentos/química , Proteínas dos Microfilamentos/genética , Fosfoproteínas/química , Fosfoproteínas/genética , Ligação Proteica , Venenos de Escorpião/química , Venenos de Escorpião/isolamento & purificação
5.
Cancer Med ; 7(8): 3875-3888, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29968965

RESUMO

Breast cancer was the highest incidence of tumor in women, which seriously threaten women's health. Our previous study found that the expression of IQUB (IQ motif and ubiquitin domain containing) was significantly increased in the development of breast cancer by transcriptome sequencing. However, there were no studies on the mechanism of IQUB in tumorigenesis. Further study showed that IQUB expression was significantly increased in breast cancer, which had a significantly positive correlation with pathological differentiation of breast cancer by tissue microarray analysis. Furthermore, we also discovered that IQUB overexpression could obviously promote the proliferation and migration of MCF-7 cells and increase the proportion of MCF-7 cells in S and G2/M phase in vitro study, while knockdown of IQUB caused inhibition of cell proliferation and migration in MDA-MB-231 cells and increased the proportion of MDA-MB-231 cells in G1 phase. Furthermore, IQUB overexpression or knockdown combined with treatment of Licl or MG-132 showed that IQUB activated Akt to promote GSK3ß phosphorylation, which in turn activated Wnt/ß-catenin signaling pathway in breast cancer cells. Taken together, these results indicated that upregulated IQUB promoted breast cancer cell proliferation and migration via activating Akt/GSK3ß/ß-catenin signaling pathway, which played an important part in the tumorigenesis and development of breast cancer.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Adulto , Idoso , Apoptose/genética , Neoplasias da Mama/diagnóstico , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Modelos Biológicos , Gradação de Tumores , Estadiamento de Neoplasias , Via de Sinalização Wnt
6.
World J Gastroenterol ; 13(9): 1445-8, 2007 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-17457979

RESUMO

AIM: To investigate the effects of KN-93, a CaMKII selective inhibitor on cell proliferation and the expression of p53 or p21 protein in human hepatic stellate cells. METHODS: Human hepatic stellate cells (LX-2) were incubated with various concentrations (0-50 micromol/L) of KN-93 or its inactive derivative, KN-92. Cell proliferation was measured by CCK-8 assay, and the expression of two cell cycle regulators, p53 and p21, was determined by SDS-PAGE and Western blotting. RESULTS: KN-93 (5-50 micromol/L) decreased the proliferation of human hepatic stellate cells in a dose-dependent manner from 81.76% (81.76% +/- 2.58% vs 96.63% +/- 2.69%, P < 0.05) to 27.15% (27.15% +/- 2.86% vs 96.59% +/- 2.44%, P < 0.01) after 24 h treatment. Incubation of 10 micromol/L KN-93 induced the cell growth reduction in a time-dependent manner from 78.27% at 8 h to 11.48% at 48 h. However, KN-92, an inactive derivative of KN-93, did not inhibit cell proliferation effectively. Moreover, analysis of cell cycle regulator expression revealed that KN-93 rather than KN-92 reduced the expression of p53 and p21. CONCLUSION: KN-93 has potent inhibitory effect on proliferation of LX-2 cells by modulating the expression of two special cell cycle regulators, p53 and p21.


Assuntos
Benzilaminas/farmacologia , Proteínas Quinases Dependentes de Cálcio-Calmodulina/antagonistas & inibidores , Proliferação de Células/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Sulfonamidas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Linhagem Celular , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Hepatócitos/citologia , Hepatócitos/metabolismo , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
7.
Cell Res ; 16(4): 389-93, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16617334

RESUMO

Recent advances in the evolutionary genetics of sex determination indicate that the only molecular similarity in sex determination found so far among phyla is between the fly doublesex, worm mab-3 and vertebrate DMRT1(dsx- and mab3-related transcription factor 1) /DMY genes. Each of these factors encodes a zinc-finger-like DNA-binding motif, DM domain. Insights into the evolution and functions of human DMRT1 gene could reveal evolutionary mechanisms of sexual development. Here we report the identification and characterization of multiple isoforms of human DMRT1 in the testis. These transcripts encode predicted proteins with 373, 275 and 175 amino acids and they were generated by alternative splicing at 3' region. Expression level of DMRT1a is higher than those of both DMRT1b and c, and the DMRT1c expression was the lowest in testis, based on comparisons of mean values from real-time fluorescent quantitative RT-PCR analysis. Both DMRT1b and c result from exonization of intronic sequences, including the exonization of an Alu element. A further search for Alu elements within the DMRT1 gene demonstrated that all 99 Alu elements are non-randomly distributed among the non-coding regions on both directions. These new characteristics of DMRT1 would have an important impact on the evolution of sexual development mechanisms.


Assuntos
Testículo/metabolismo , Fatores de Transcrição/genética , Processamento Alternativo , Elementos Alu/genética , Sequência de Aminoácidos , Éxons , Variação Genética , Humanos , Íntrons , Masculino , Dados de Sequência Molecular , Isoformas de Proteínas/metabolismo
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