RESUMO
Background: Perioperative multimodal analgesia can prevent chronic pain after breast cancer surgery. This study aimed to investigate the efficacy of combined perioperative oral pregabalin and postoperative esketamine in preventing chronic pain after breast cancer surgery. Methods: Ninety patients undergoing elective breast cancer surgery were randomized into the combined pregabalin and esketamine group (EP group) and the general anesthesia alone group (Control group). The EP group received 150 mg of oral pregabalin 1 h before surgery and twice daily for seven days postoperatively, and a patient-controlled analgesia pump after surgery that delivered 100 µg sufentanil + 1.25 mg/kg esketamine + 4 mg tropisetron in 100 mL saline solution intravenously. The Control group received placebo capsules before and after the surgery and routine postoperative analgesia (100 µg sufentanil + 4 mg tropisetron in 100 mL saline solution). The primary outcome was the incidence of chronic pain three and six months after surgery. Secondary outcomes included acute postoperative pain, postoperative opioid consumption, and incidence of adverse events. Results: The incidence of chronic pain in the EP group was significantly lower than in the Control group three (14.3% vs 46.3%, P = 0.005) and six (7.1% vs 31.7%, P = 0.009) months postoperatively. The rest numerical rating scale (NRS) pain scores 1-3 days postoperatively and coughing NRS pain scores 1-7 days postoperatively in the EP group were significantly lower than in the Control group (all P Ë 0.05). The cumulative sufentanil consumption in the EP group during postoperative 0-12, 12-24, and 24-48, 0-24, and 0-48 hours were significantly lower than in the Control group (all P Ë 0.05). Conclusion: Combined perioperative oral pregabalin and postoperative esketamine effectively prevented chronic pain after breast cancer surgery, improved acute postoperative pain, and reduced postoperative opioid consumption.
Assuntos
Neoplasias da Mama , Dor Crônica , Humanos , Feminino , Neoplasias da Mama/cirurgia , Pregabalina/uso terapêutico , Analgésicos Opioides , Dor Crônica/tratamento farmacológico , Dor Crônica/prevenção & controle , Solução Salina , Sufentanil/uso terapêutico , Tropizetrona , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/prevenção & controleRESUMO
BACKGROUND: Hypoxaemia is frequently seen during flexible bronchoscopies that are done with a nasal approach under the traditional sedation with propofol. This study investigated the potential benefits of supraglottic jet oxygenation and ventilation (SJOV) using the Wei nasal jet tube (WNJ) in reducing hypoxaemia in patients undergoing bronchoscopy under moderate to deep intravenous sedation using a propofol, lidocaine and remifentanil cocktail. OBJECTIVES: Our primary objective was to evaluate the efficacy and complications of SJOV via the WNJ during flexible bronchoscopy under moderate to heavy sedation with propofol and remifentanil. DESIGN: A randomised controlled clinical trial. SETTING: The 180th Hospital of People's Liberation Army, Quanzhou, China, from 1 June to 1 November 2019. PATIENTS: A total of 280 patients aged ≥18 years with American Society of Anesthesiologists' physical status 1 to 3 undergoing flexible bronchoscopy were studied. INTERVENTIONS: Patients were assigned randomly into one of two groups, a nasal cannula oxygenation (NCO) group (nâ=â140) using a nasal cannula to deliver oxygen (4 l min-1) or the SJOV group (nâ=â140) using a WNJ connected to a manual jet ventilator to provide SJOV at a driving pressure of 103 kPa, respiratory rate 20 min-1, FiO2 1.0 and inspiratory:expiratory (I:E) ratio 1:2. MAIN OUTCOME MEASURES: The primary outcome was an incidence of desaturation (defined as SpO2â<â90%) during the procedure. Other adverse events related to the sedation or SJOV were also recorded. RESULTS: Compared with the NCO group, the incidence of desaturation in the SJOV group was lower (NCO 37.0% vs. SJOV 13.1%) (Pâ<â0.001). Patients in the SJOV group had a higher incidence of a dry mouth at 1âmin (13.1% vs. 1.5%, Pâ<â0.001) than at 30âmin (1.5% vs. 0%, Pâ=â0.159) or at 24âh (0% vs. 0%). There was no significant difference between the groups in respect of sore throat, subcutaneous emphysema or nasal bleeding. CONCLUSIONS: SJOV via a WNJ during flexible bronchoscopy under moderate to deep sedation with propofol and remifentanil significantly reduces the incidence of desaturation when compared with regular oxygen supplementation via a nasal cannula. Patients in the SJOV group had an increased incidence of transient dry mouth. TRIAL REGISTRATION: Registered at www.chictr.org.cn (ChiCTR1900023514).
Assuntos
Sedação Profunda , Propofol , Adolescente , Adulto , Broncoscopia , China , Humanos , Propofol/efeitos adversos , RemifentanilRESUMO
BACKGROUND: To investigate the effectiveness and rationality of different administration modes of dexmedetomidine with 0.5% ropivacaine on intercostal nerve block. METHODS: In total, 150 patients aged from 20-45 years with a body mass index (BMI): 18.5-23.9 kg/m2, met the criteria from the American Society of Anesthesiologists (ASA) class: I-II, and underwent lumpectomy in our center were equally randomized into three groups using a table of random numbers. Group D1: perineural administration of dexmedetomidine 0.5 µg/kg + intercostal nerve block with 0.5% ropivacaine; group D2: intravenous infusion of dexmedetomidine0.5 µg/kg + intercostal nerve block with 0.5% ropivacaine; and group R: intercostal nerve block with 0.5% ropivacaine. The Numerical Rating Scale (NRS) of pain and the Ramsay Sedation Scale were used for assessing pain and sedation levels 4, 8, 12, and 24 hours after the operation. The total duration of analgesia, total requirement of rescue analgesia, and adverse reactions were recorded. RESULTS: The NRS scores in groups D1 and D2 were significantly lower than that in group R, 8 hours after the operation (both P<0.05), and the NRS score in group D1 was significantly lower than in group D2 12 hours after the operation (P<0.05). The Ramsay scores showed no significant differences among all three groups at all time points after surgery. The duration of analgesia in group D1 was significantly longer than in group D2 (P<0.05). No rescue analgesia was needed in all three groups, and no adverse reactions such as dizziness, dry mouth, nausea, vomiting, and respiratory depression were reported. CONCLUSIONS: The combinations of dexmedetomidine with ropivacaine for intercostal nerve blocking can prolong the duration of analgesia after lumpectomy; however, the duration of analgesia is longer via the perineural route than via the intravenous route.
Assuntos
Analgesia/métodos , Anestésicos Locais/administração & dosagem , Dexmedetomidina/administração & dosagem , Bloqueio Nervoso/métodos , Dor Pós-Operatória/prevenção & controle , Ropivacaina/administração & dosagem , Adulto , Analgésicos não Narcóticos/administração & dosagem , Feminino , Humanos , Nervos Intercostais/efeitos dos fármacos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
Dishevelled-associated activator of morphogenesis 1 (Daam1) is a formin protein and participates in regulating cell migration of triple-negative breast cancer (TNBC) cells. The specific miRNA targeting Daam1 and mediating cell migration and invasion remains obscure. This experiment investigated the suppressive role of miR-613 in TNBC cells. The luciferase activity of Daam1 3'-untranslated region (3'-UTR) based reporters constructed in HEK-293T and MCF-7 cells suggested that Daam1 was the target gene of miR-613. Overexpressed miR-613 reduced the protein level of Daam1, weakened RhoA activity, and retarded the cell migration, cell invasion and colony formation of TNBC cells. Overexpression of Daam1 or RhoA rescued cell migration and invasion in miR-613-overexpressed TNBC cells, but failed to reverse colony formation. MiR-613 was significantly downregulated in breast cancer tissues compared with that in adjacent normal tissues. This downregulation in TNBC tissues and lymphnode metastatic breast cancer tissues was more obvious than that in non-TNBC tissues and non-metastatic cancer tissues, respectively. MiR-613 weakens the resistance of TNBC cells against paclitaxel rather than adriamycin, cyclophosphamide, docetaxel, and kaempferol. Taken together, miR-613 is involved in cell migration and invasion of TNBC cells via targeting Daam1/RhoA signaling pathway.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , MicroRNAs/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proteína rhoA de Ligação ao GTP/metabolismo , Regiões 3' não Traduzidas , Linhagem Celular Tumoral , Movimento Celular , Ciclofosfamida/farmacologia , Docetaxel/farmacologia , Regulação para Baixo , Doxorrubicina/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Humanos , Quempferóis/farmacologia , Metástase Linfática , Células MCF-7 , Proteínas dos Microfilamentos , Invasividade Neoplásica , Paclitaxel/farmacologia , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/metabolismo , Proteínas rho de Ligação ao GTPRESUMO
PURPOSE: Triple-negative breast cancer (TNBC) is an especially aggressive and hard-to-treat disease. Although the anticancer role of kaempferol has been reported in breast cancer, the effect of kaempferol on TNBC remains unclear. MATERIALS AND METHODS: This experiment investigated the migration-suppressive role of a low dose of kaempferol in TNBC cells. Wound-healing assays and cell invasion assays were used to confirm the migration and invasion of cells treated with kaempferol or transfected indicated constructs. We evaluated the activations of RhoA, Rac1 and Cdc42 in TNBC cells with a Rho activation assay. A panel of inhibitors of estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 (ER/PR/HER2) treated non-TNBC (SK-BR-3 and MCF-7) cells and blocked the ER/PR/HER2 activity. Wound-healing assays and Rho activation assays were employed to measure the effect of kaempferol and ER/PR/HER2 inhibitors on Rho activation and cell migration rates. RESULTS: A low dose of kaempferol (20 µmol/L) had a potent inhibitory effect on the migration and invasion of TNBC cells, but not on the migration of non-TNBC (SK-BR-3 and MCF-7) cells. The low dose of kaempferol downregulated the activations of RhoA and Rac1 in TNBC cells. Moreover, the low dose of kaempferol also inhibited the migration and RhoA activations of HER2-silence SK-BR-3 and ER/PR-silence MCF-7 cells. Overexpressed HER2 rescued the cell migration and RhoA and Rac1 activations of kaempferol-treated MDA-MB-231 cells. CONCLUSION: The low dose of kaempferol inhibits the migration and invasion of TNBC cells via blocking RhoA and Rac1 signaling pathway.
RESUMO
Different hepatitis C virus (HCV) genotypes exhibit differences in disease pathogenesis and progression, as well as disease outcomes and response to therapy. Tracking the change of HCV genotypes in various epidemiological settings is critical for both disease surveillance and the development of improved antiviral treatment. Here, we tracked the changes in the prevalence of the HCV genotypes in China between 2004-2007 and 2008-2011. HCV-RNA-positive sera were collected from volunteer blood donors during the period 2008-2011. The genotypes were determined by phylogenic analysis using the NS5B and E1 sequences. Geographical and demographic distribution patterns related to the HCV genotypes obtained in 2008-2011 were compared with our previous study, which recorded data in the period 2004-2007. Pearson chi-square test and t-test were used to statistically analyze the results. In 2008-2011, HCV subtypes 1b and 6a were detected in 43.8 % (184/420) and 34.3 % (144/420), respectively. The male/female ratio was found to be higher for HCV genotype 6 than for genotypes 1 and 2. When compared with the period of 2004-2007, although no significant difference was found in gender or age for genotypes 1, 2, 3 and 6, the subtype 6a frequency was significantly increased from 11 % to 26.5 % in the blood donors from outside of Guangdong Province in 2008-2011. A pattern of increase in HCV subtype 6a was found in blood donors outside of Guangdong Province, indicating that HCV subtype 6a has rapidly spread from Guangdong to other regions of China over the past 10 years.
Assuntos
Hepacivirus/classificação , Hepacivirus/isolamento & purificação , Hepatite C/epidemiologia , Hepatite C/virologia , China/epidemiologia , Demografia , Genótipo , Hepacivirus/genética , Humanos , Filogeografia , Prevalência , Análise de Sequência de DNA , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genéticaRESUMO
We previously reported that sphingosine kinase 1 (SphK1), an enzyme that catalyzes the production of sphingosine-1-phosphate (SIP), is upregulated in human gastric cancer and predicts poor clinical outcome. In the present study, we used known differential effects of UV irradiation on human MGC-803 gastric cancer cells to determine their effect on SphK1 activity. Ectopic expression of SphK1 in MGC-803 gastric cancer cells markedly enhanced their resistance to UV irradiation, whereas silencing endogenous SphK1 with shRNAs weakened this ability. Furthermore, these anti-apoptotic effects were significantly associated with decrease of Bim, an apoptosis-related protein. We further demonstrated that SphK1 could downregulate the transcriptional activity of forkhead box O3a (FoxO3a) by inducing its phosphorylation, which was found to be associated with the PI3K/Akt signaling. Taken together, our study supports the theory that SphK1 confers resistance to apoptosis in gastric cancer cells via the Akt/FoxO3a/Bim pathway.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/genética , Carcinoma/genética , Fatores de Transcrição Forkhead/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Membrana/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Neoplasias Gástricas/genética , Raios Ultravioleta , Proteína 11 Semelhante a Bcl-2 , Carcinoma/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/metabolismo , Inativação Gênica , Humanos , Lisofosfolipídeos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , RNA Interferente Pequeno , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para CimaRESUMO
UNLABELLED: We investigated the migration patterns of hepatitis C virus (HCV) in China. Partial E1 and/or NS5B sequences from 411 volunteer blood donors sampled in 17 provinces and municipalities located in five large regions, the north-northeast, northwest, southwest, central south, and southeast, were characterized. The sequences were classified into eight subtypes (1a, n = 3; 1b, n = 183; 2a, n = 83; 3a, n = 30; 3b, n = 44; 6a, n = 55; 6n, n = 10; 6v, n = 1) and a new subtype candidate. Bayesian evolutionary analysis by sampling trees of the E1 sequences of the five major subtypes revealed distinct migration patterns. Subtype 1b showed four groups: one is prevalent nationwide with possible origins in the north-northeast; two are locally epidemic in the central south and northwest, respectively, and have spread sporadically to other regions; and the fourth one is likely linked to the long-distance dispersion among intravenous drug users from the northwest. Subtype 2a showed two groups: the larger one was mainly restricted to the northwest and seemed to show a trend toward migration via the Silk Road; the smaller one was geographically mixed and may represent descendants of those that spread widely during the contaminated plasma campaign in the 1990s. Subtype 3a exhibited three well-separated geographic groups that may be epidemically unrelated: one showed origins in the northwest, one showed origins in the southwest, and the other showed origins in the central south. In contrast, subtype 3b had a mixture of geographic origins, suggesting migrations from the southwest to the northwest and sporadically to other regions. Structurally resembling the tree for subtype 3a, the tree for subtype 6a showed four groups that may indicate migrations from the central south to southeast, southwest, and northwest. Strikingly, no subtype 6a strain was identified in the north-northeast. IMPORTANCE: With a population of greater than 1.3 billion and a territory of >9.6 million square kilometers, China has a total of 34 provinces and municipalities. In such a vast country, the epidemic history and migration trends of HCV are thought to be unique and complex but variable among regions and are unlikely to be represented by those observed in only one or at best a few provinces and municipalities. However, due to the difficulties in recruiting patients, all previous studies for this purpose have been based only on data from limited regions, and therefore, geographical biases were unavoidable. In this study, such biases were greatly reduced because we utilized samples collected from volunteer blood donors in 17 provinces and municipalities. To our knowledge, this is the first study in which the HCV isolates represented such a large portion of the country, and thus, the results should shed light on the current understanding of HCV molecular epidemiology.
Assuntos
Doadores de Sangue , Fluxo Gênico/genética , Hepacivirus/genética , Hepatite C/epidemiologia , China/epidemiologia , Genótipo , Hepacivirus/classificação , Hepacivirus/isolamento & purificação , Hepatite C/virologia , Humanos , Epidemiologia Molecular , Filogenia , Filogeografia , Prevalência , RNA Viral/genética , Análise de Sequência de DNA , Proteínas do Envelope Viral/genética , Proteínas não Estruturais Virais/genética , VoluntáriosRESUMO
PURPOSE: The present study was to examine the effect of sphingosine kinase-1 (SPHK1) on chemotherapeutics-induced apoptosis in non-small cell lung cancer (NSCLC) cells, which is relatively insensitive to chemotherapy, and its clinical significance in NSCLC progression. EXPERIMENTAL DESIGN: The correlation of SPHK1 expression and clinical features of NSCLC was analyzed in 218 paraffin-embedded archived NSCLC specimens by immunohistochemical analysis. The effect of SPHK1 on apoptosis induced by chemotherapeutics was examined both in vitro and in vivo, using Annexin V staining and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) assays. Western blotting and luciferase analysis were performed to examine the impact of SPHK1 on the PI3K/Akt/NF-κB signaling. RESULTS: The expression of SPHK1 was markedly increased in NSCLC and correlated with tumor progression and poor survival of patients with NSCLC. Upregulation of SPHK1 significantly inhibited doxorubicin- or docetaxel-induced apoptosis, associated with induction of antiapoptotic proteins Bcl-xl, c-IAP1, c-IAP2, and TRAF1. In contrast, silencing SPHK1 expression or inhibiting SPHK1 activity with specific inhibitor, SK1-I, significantly enhanced the sensitivity of NSCLC cells to apoptosis induced by chemotherapeutics both in vitro and in vivo. Moreover, we demonstrated that upregulation of SPHK1 activated the PI3K/Akt/NF-κB pathway, and that inhibition of the PI3K/Akt/NF-κB pathway abrogated the antiapoptotic effect of SPHK1 on NSCLC cells. CONCLUSIONS: Our results suggest that SPHK1 is a potential pharmacologic target for the treatment of NSCLC and inhibition of SPHK1 expression or its kinase activity might represent a novel strategy to sensitize NSCLC to chemotherapy.
Assuntos
Apoptose , Carcinoma Pulmonar de Células não Pequenas/patologia , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/patologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Antineoplásicos/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Técnicas de Cultura de Células , Linhagem Celular Tumoral , Proliferação de Células , Docetaxel , Tolerância a Medicamentos/genética , Feminino , Genes Reporter , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Luciferases de Renilla/biossíntese , Luciferases de Renilla/genética , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Interferência de RNA , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Taxoides/farmacologia , Transplante HeterólogoRESUMO
BACKGROUND: Overexpression of sphingosine kinase-1 (SPHK1) has been demonstrated to be associated with the development and progression in various types of human cancers. The current study was to characterize the expression of SPHK1 in salivary gland carcinomas (SGC) and to investigate the association between SPHK1 expression and progression of SGC. METHODS: The expression of SPHK1 was examined in 2 normal salivary gland tissues, 8 SGC tissues of various clinical stages, and 5 pairs of primary SGC and adjacent salivary gland tissues from the same patient, using real-time PCR and western blot analysis. Furthermore, the SPHK1 protein expression was analyzed in 159 clinicopathologically characterized SGC cases by immunohistochemistry. Statistical analyses were performed to determine the prognostic and diagnostic associations. RESULTS: SPHK1 expression was found to be markedly upregulated in SGC tissues than that in the normal salivary gland tissues and paired adjacent salivary gland tissues, at both mRNA and protein levels. Statistical analysis revealed a significant correlation of SPHK1 expression with the clinical stage (P = 0.005), T classification (P = 0.017), N classification (P = 0.009), M classification (P = 0.002), and pathological differentiation (P = 0.013). Patients with higher SPHK1 expression had shorter overall survival time, whereas patients with lower SPHK1 expression had better survival. Importantly, patients in the group without adjuvant therapy who exhibited high SPHK1 expression had significantly lower overall survival rates compared with those with low SPHK1 expression. Moreover, multivariate analysis suggested that SPHK1 expression might be an independent prognostic indicator for the survival of SGC patients. CONCLUSIONS: Our results suggest that SPHK1 expression is associated with SGC progression, and might represent as a novel and valuable predictor for adjuvant therapy to SGC patients.
Assuntos
Biomarcadores Tumorais/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Neoplasias das Glândulas Salivares/metabolismo , Glândulas Salivares/metabolismo , Adenocarcinoma Papilar/genética , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patologia , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/metabolismo , Carcinoma de Células Acinares/patologia , Carcinoma Adenoide Cístico/genética , Carcinoma Adenoide Cístico/metabolismo , Carcinoma Adenoide Cístico/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Raios gama , Humanos , Técnicas Imunoenzimáticas , Masculino , Pessoa de Meia-Idade , Tumor Mucoepidermoide/genética , Tumor Mucoepidermoide/metabolismo , Tumor Mucoepidermoide/patologia , Cuidados Paliativos , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Prognóstico , RNA Mensageiro/genética , Radioterapia Adjuvante , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Glândulas Salivares/patologia , Taxa de SobrevidaRESUMO
The biosynthesis and metabolism of RNA play important roles in regulating gene expression. On the other hand, it has been shown that RNA expression profiling is differentially distinct between cancer and normal cells, suggesting the possibility that aberrant regulation of RNA metabolism might be associated with the development and progression of cancer. In the current study, we found that Sam68, an RNA-binding protein that links cellular signalling to RNA processing, was markedly overexpressed in breast cancer cells and tissues. Immunohistochemical analysis showed that the expression and cytoplasmic localization of Sam68 significantly correlated with clinical characteristics of patients, including clinical stage, tumour-nodule-metastasis (TNM) classification, histological grade, and ER expression. Univariate and multivariate analyses showed that the expression level and cytoplasmic localization of Sam68 were identified as independent prognostic factors. Furthermore, we found that siRNA knockdown of endogenous Sam68 inhibited cell proliferation and tumourigenicity of breast cancer cells in vitro, through blocking the G1 to S phase transition. Moreover, we demonstrated that the anti-proliferative effect of silencing Sam68 on breast cancer cells was associated with up-regulation of cyclin-dependent kinase inhibitor p21(Cip1) and p27(Kip1), enhanced transactivation of FOXO factors, and attenuation of Akt/GSK-3ß signalling. Taken together, our results suggest that Sam68 might play an important role in promoting the proliferation and carcinogenesis of human breast cancer, and thereby might be a novel and useful prognostic marker and a potential target for human breast cancer treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Proliferação de Células , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas de Ligação a RNA/genética , Células Tumorais Cultivadas , Regulação para CimaRESUMO
Previously, we have identified a novel centrosomal protein centrobin that asymmetrically localizes to the daughter centriole. We found that depletion of centrobin expression inhibited the centriole duplication and impaired cytokinesis. However, the biological significance of centrobin in the cell cycle remains unknown. In the current study, we observed that silencing centrobin significantly inhibited the proliferation of lung cancer cell A549 and prevented the cells from G1 to S transition, whereas the growth rate of lung cancer cell line H1299, a p53-null cell line, was not affected. Furthermore, we demonstrated that the G1-S-phase arrest induced by centrobin knockdown in A549 cells is mediated by the upregulation of cell-cycle regulator p53, which is associated with the activation of cellular stress induced p38 pathway instead of DNA damage induced ATM pathway. Inhibition of p38 activity or downregulation of p38 expression could overcome the cell-cycle arrest caused by centrobin depletion. Taken together, our current findings demonstrated that centrobin plays an important role in the progression of cell cycle, and a tight association between the cell-cycle progression and defective centrosomes caused by depletion of centrobin.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Ciclo Celular , Centríolos/enzimologia , Proteína Supressora de Tumor p53/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Bromodesoxiuridina/metabolismo , Contagem de Células , Linhagem Celular Tumoral , Proliferação de Células , Fase G1 , Técnicas de Silenciamento de Genes , Humanos , Antígeno Ki-67/metabolismo , Fase S , Transdução de SinaisRESUMO
FOXO transcription factors are key tumor suppressors in mammalian cells. Until now, suppression of FOXOs in cancer cells was thought to be mainly due to activation of multiple onco-kinases by a phosphorylation-ubiquitylation-mediated cascade. Therefore, it was speculated that inhibition of FOXO proteins would naturally occur through a multiple step post-translational process. However, whether cancer cells may downregulate FOXO protein via an alternative regulatory mechanism is unclear. In the current study, we report that expression of miR-96 was markedly upregulated in breast cancer cells and breast cancer tissues compared with normal breast epithelial cells (NBEC) and normal breast tissues. Ectopic expression of miR-96 induced the proliferation and anchorage-independent growth of breast cancer cells, while inhibition of miR-96 reduced this effect. Furthermore, upregulation of miR-96 in breast cancer cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-96 downregulated FOXO3a expression by directly targeting the FOXO3a 3'-untranslated region. Taken together, our results suggest that miR-96 may play an important role in promoting proliferation of human breast cancer cells and present a novel mechanism of miRNA-mediated direct suppression of FOXO3a expression in cancer cells.