RESUMO
MicroRNAs can act as tumour suppressors or oncogenes by regulating cellular differentiation, proliferation and apoptosis, and the dysregulation of miRNA is involved in the occurrence and development of NSCLC. Here, we provided evidence that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT. We found that miR-92b was up-regulated in human NSCLC tissues and cell lines. MiR-92b knockdown suppressed the NSCLC cells proliferation and migration in both in vivo and in vitro models. Conversely, miR-92b overexpression induced an aggressive phenotype. Moreover, miR-92b-mediated regulation of NSCLC cell proliferation and migration depended on binding to PTEN mRNA, which then led to the degradation of PTEN and activation of the downstream AKT signalling pathway. Overall, this study revealed the oncogenic roles of miR-92b in NSCLC by targeting PTEN/AKT, and provided novel insights for future treatments of NSCLC patients. SIGNIFICANCE OF THE STUDY: MiR-92b was up-regulated in human NSCLC tissues and cell lines. Our study demonstrated that miR-92b as an oncogene in NSCLC by targeting PTEN/AKT in both in vivo and in vitro models and provided novel insights for future treatments of NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Oncogenes , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Neoplásico/metabolismo , Células A549 , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Neoplasias Pulmonares/genética , MicroRNAs/genética , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Neoplásico/genéticaRESUMO
Oridonin could induce NB (neuroblastoma) cells growth inhibition by inducing apoptosis and cell cycle arrest, and the molecular mechanisms behind the effects deserve to be further explored. Here, oridonin was confirmed to cause the reactivation of p53 (cellular tumor antigen p53) to promote the expression of a series of apoptosis- and cell cycle arrest-related proteins for the biological effects. During the process, oridonin relied on the caspase activation to cleave p53-induced Mdm2 (E3 ubiquitin-protein ligase Mdm2) to generate Mdm2-p60. The generation of Mdm2-p60 stabilized p53, and resulted in p53 accumulation for p53 continuous activation. In our research, it was also found that the reactivation of p53 induced by oridonin was closely related with the generation of ROS (reactive oxygen species). Taken together, these findings explain that oridonin exerts its anticancer activity partially by targeting the Mdm2-p53 axis in NB cells, which lay an experimental base for future research of exploring the effects and molecular mechanisms of oridonin.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/genética , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/genética , Diterpenos do Tipo Caurano/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteína Supressora de Tumor p53/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Modelos Biológicos , Neuroblastoma , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Synthetic CpG oligodeoxynucleotides(CpG ODN) containing unmethylated CpG dinucleotide motifs, which mimic the effects of bacterial DNA, can stimulate the host's immune defense to reject cancer cells as "non-self" signal. This study was to evaluate the antitumor effect of CpG ODN against human neuroblastoma xenografts in nude mice depending on the innate immunity. METHODS: The cytotoxicity of CpG ODN on neuroblastoma SK-N-MC cells was detected by WST-1 assay in vitro. Neuroblastoma xenografts were built subcutaneously in nude mice. When palpable tumor developed, the mice were randomized into normal saline (NS), non-CpG ODN, and CpG ODN groups (each group contained six mice), and were administered every other day for two weeks. When tumor grew to 5 cm3, the mice were killed to observe tumor morphology by histology and histochemistry. RESULTS: CpG ODN had no cytotoxicity on SK-N-MC cells in vitro. Tumor volume was significantly smaller in CpG ODN group than in NS and non-CpG ODN groups at the end of the observation [(0.14+/-0.03) cm3 vs. (2.97+/-0.40) cm3 and (3.80+/-1.12) cm3, P<0.01]. On HE-stained sections, the tumor tissues of CpG ODN group showed intratumoral infiltration of inflammatory cells and large areas of necrosis, whereas those of controls showed less infiltration and no necrosis. By immunohistochemistry, the tumor tissues of CpG ODN group showed more natural killer (NK) cells and macrophages as compared with those of control groups. CONCLUSION: CpG ODN may have therapeutic effect on neuroblastoma in nude mice via mediating the activity of NK cells and macrophages.
