RESUMO
The dysregulation of miR-532-5p is involved in the development of several cancers. Nevertheless, the roles of miR-532-5p in osteosarcoma (OS) have yet to be illuminated. In the present study, we found that miR-532-5p was significantly downregulated in both OS tissues and cell lines. The low level of miR-532-5p was associated with advance clinical stage and poor overall survival in patient with OS. The functional experiments implied that upregulation of miR-532-5p restrained OS U2OS cell growth and metastatic ability in vitro; induced apoptosis, and impaired OS cell growth in vivo. Mechanistically, chemokine (C-X-C Motif) ligand 2 (CXCL2) was proved as a target gene of miR-532-5p. The inhibitory effects of miR-532-5p on OS cell were rescued by CXCL2 overexpression. Altogether, we demonstrated that miR-532-5p exerted tumor-inhibitory functions in OS cell via regulating CXCL2.
Assuntos
Neoplasias Ósseas/genética , Quimiocina CXCL2/genética , MicroRNAs/genética , Osteossarcoma/genética , Adolescente , Adulto , Antagomirs/genética , Antagomirs/metabolismo , Apoptose/genética , Pareamento de Bases , Sequência de Bases , Neoplasias Ósseas/diagnóstico , Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/mortalidade , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Linhagem Celular Tumoral , Proliferação de Células , Quimiocina CXCL2/agonistas , Quimiocina CXCL2/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oligorribonucleotídeos/genética , Oligorribonucleotídeos/metabolismo , Osteossarcoma/diagnóstico , Osteossarcoma/metabolismo , Osteossarcoma/mortalidade , Fenótipo , Plasmídeos/química , Plasmídeos/metabolismo , Prognóstico , Transdução de Sinais , Análise de SobrevidaRESUMO
The compound 5-fluorouracil (5-FU) is used in cancer chemotherapy and is known to cause diarrhoea. We recently reported that chemokine (C-X-C motif) ligand 1 (CXCL1) and neutrophils in the colonic mucosa were markedly increased by the administration of 5-FU in mice. Curcumin has anti-inflammatory, antitumour and antioxidant properties. Therefore, we examined the effect of curcumin on 5-FU-induced diarrhoea development and CXCL1 and CXCL2 up-regulation in the colon. Mice were given 5-FU (50 mg/kg, i.p.) daily for 4 days. Curcumin (100 or 300 mg/kg, p.o.) was administered on the day before the first administration of 5-FU and administered 30 min. before the administration of 5-FU. Gene expression levels of CXCL1 and CXCL2 in the colon were examined by real-time RT-PCR. Curcumin reduced the 5-FU-induced diarrhoea development. Under this condition, the CXCL1 and CXCL2 gene up-regulated by 5-FU administration was inhibited by curcumin. The gene expression of CXCL1 and CXCL2 was also enhanced by 5-FU application in vitro. The 5-FU-induced up-regulated CXCL1 and CXCL2 gene expressions were inhibited by curcumin, Bay-117082 and bortezomib, nuclear factor kappa B (NF-κB) inhibitors, C646, a p300/cyclic adenosine monophosphate response element-binding protein-histone acetyltransferase (HAT) inhibitor. In conclusion, these findings suggested that curcumin prevented the development of diarrhoea by inhibiting NF-κB and HAT activation.
Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Antioxidantes/uso terapêutico , Colo Descendente/efeitos dos fármacos , Curcumina/uso terapêutico , Diarreia/prevenção & controle , Suplementos Nutricionais , Fluoruracila/efeitos adversos , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/farmacologia , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Quimiocina CXCL1/agonistas , Quimiocina CXCL1/antagonistas & inibidores , Quimiocina CXCL1/genética , Quimiocina CXCL1/metabolismo , Quimiocina CXCL2/agonistas , Quimiocina CXCL2/antagonistas & inibidores , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Colo Descendente/imunologia , Colo Descendente/metabolismo , Colo Descendente/fisiopatologia , Curcumina/administração & dosagem , Curcumina/farmacologia , Diarreia/induzido quimicamente , Diarreia/metabolismo , Diarreia/fisiopatologia , Proteína p300 Associada a E1A/agonistas , Proteína p300 Associada a E1A/antagonistas & inibidores , Proteína p300 Associada a E1A/metabolismo , Inibidores Enzimáticos/farmacologia , Fluoruracila/antagonistas & inibidores , Fluoruracila/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , NF-kappa B/agonistas , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Índice de Gravidade de Doença , Técnicas de Cultura de TecidosRESUMO
We had previously shown that microcystin-LR (MCLR) could induce lung and liver inflammation after acute exposure. The biological outcomes following prolonged exposure to MCLR, although more frequent, are still poorly understood. Thus, we aimed to verify whether repeated doses of MCLR could damage lung and liver and evaluate the dose-dependence of the results. Male Swiss mice received 10 intraperitoneal injections (i.p.) of distilled water (60 µL, CTRL) or different doses of MCLR (5 µg/kg, TOX5), 10 µg/kg (TOX10), 15 µg/kg (TOX15) and 20 µg/kg (TOX20) every other day. On the tenth injection respiratory mechanics (lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance) was measured. Lungs and liver were prepared for histology (morphometry and cellularity) and inflammatory mediators (KC and MIP-2) determination. All mechanical parameters and alveolar collapse were significantly higher in TOX5, 10, 15 and 20 than CTRL, but did not differ among them. Lung inflammatory cell content increased dose-dependently in all TOX groups in relation to CTRL, being TOX20 the largest. The production of KC was increased in lung and liver homogenates. MIP-2 increased in the liver of all TOX groups, but in lung homogenates it was significantly higher only in TOX20 group. All TOX mice livers showed steatosis, necrosis, inflammatory foci and a high degree of binucleated hepatocytes. In conclusion, sub-chronic exposure to MCLR damaged lung and liver in all doses, with a more important lung inflammation in TOX20 group.
