RESUMO
As the first clinical proteasome inhibitor, Bortezomib (BTZ) has been reported to improve the outcome of lymphoma. However, due to the unstable property, low bioavailability, and hydrophobic properties of BTZ, it is needed to develop effective drug delivery systems to deliver BTZ into targeted cells or organs. Here we developed a bortezomib (BTZ)-loaded HMSNs (BTZ@HMSNs) system, which can sustain the release of BTZ in targeted tissues. In vitro assays showed that BTZ@HMSNs limited cell proliferation and augmented apoptosis of lymphoma SNK-1 cells. Moreover, BTZ@HMSNs significantly diminished migration and invasion of SNK-1 cells as compared with BTZ. In contrast to the upregulation of SHP-1, BTZ@HMSNs decreased the mRNA levels of c-Kit, NF-κB, and JAK1, which elicit oncogenic role in lymphoma development. Importantly, lymphoma mice model showed that BTZ@HMSNs significantly activated p53 signaling and reduced tumor volume and weight compared with free BTZ. Our data thus demonstrate that BTZ@HMSNs manifests improved tumor-suppressing effect in vitro and in vivo compared to free BTZ. We believe that HMSNs is a promising strategy for delivering therapeutic agents for cancer treatment.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Bortezomib/administração & dosagem , Bortezomib/farmacologia , Proliferação de Células/efeitos dos fármacos , Linfoma/tratamento farmacológico , Nanosferas , Animais , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Portadores de Fármacos , Humanos , Técnicas In Vitro , Janus Quinase 1/efeitos dos fármacos , Janus Quinase 1/genética , Linfoma/genética , Linfoma/metabolismo , Camundongos , Camundongos Nus , NF-kappa B/efeitos dos fármacos , NF-kappa B/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/efeitos dos fármacos , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-kit/genética , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/metabolismo , Dióxido de Silício , Proteína Supressora de Tumor p53/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND/AIMS: The present study aimed to explore the function of NEAT1 on non-small cell lung cancer (NSCLC), as well as its underlying mechanisms. METHODS: Quantitative realtime PCR (qRT-PCR) was used to measure NEAT1 expression in NSCLC tissues and cells. MTT assay and transwell assay were performed to detect cell proliferation, migration and invasion. Potential target genes were identified via luciferase reporter assay. Protein analysis was performed through western blotting. RESULTS: The expressions of NEAT1 were significantly higher in both of NSCLC tissues and cells than in normal controls. High expression of NEAT1 was significantly associated with TNM stage (P=0.000) and metastasis (P=0.000). NEAT1 knockdown inhibited the proliferation, migration and invasion of NSCLC cells. Hypoxia induction mediated by HIF-2α promoted EMT and NEAT1 expressions. Moreover, miR-101-3p was a target of NEAT1. We also found that SOX9 was a target of miR-101-3p. Oncogenic function of NEAT1 on NSCLC progression was mediated by miR-101-3p/SOX9/Wnt/ß-catenin signaling pathway. CONCLUSION: NEAT1 up-regulation induced by HIF-2α over-expression could promote the progression of NSCLC under hypoxic condition. Moreover, NEAT1 also takes part in NSCLC progression via miR-101-3p/SOX9/Wnt/ß-catenin axis.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição SOX9/metabolismo , Antagomirs/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição SOX9/antagonistas & inibidores , Fatores de Transcrição SOX9/genética , Via de Sinalização Wnt , beta Catenina/metabolismoRESUMO
BACKGROUND Findings regarding the association of the single-nucleotide polymorphisms (SNPs) rs4986790 and rs4986791 in Toll-like receptor 4 and rs187084, rs574386, and rs352139 in Toll-like receptor 9 (TLR9) with pulmonary tuberculosis (PTB) susceptibility are inconsistent. We conducted a meta-analysis to systematically summarize and clarify the association between these SNPs and PTB susceptibility. MATERIAL AND METHODS A systematic literature search for relevant studies up to December, 2014 was performed in PubMed, EMBASE, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wanfang databases. Information was gathered from each eligible study. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to pool the effect size. RESULTS Finally, a total of 16 case-control studies on these polymorphisms were enrolled in this meta-analysis. The meta-analysis results suggest there was no association between these polymorphisms and PTB risk PTB risk in all the genetic models overall. However, for TLR4 rs4986791, a significant increased PTB risk was found in Africans, and for TLR9 rs352139 a significant increased PTB risk was found in Asians after subgroup analysis by ethnicity, although the enrolled studies were limited. CONCLUSIONS There was no association between the polymorphisms in TLR4 and 9 and PTB risk overall, but TLR4 rs4986791 and TLR9 rs352139 might be associated with increased PTB risk in Africans and Asians, respectively. Additional well-designed, larger-scale epidemiological studies are needed to validate our results.