RESUMO
Fractal patterns have been shown to change in resting- and task-state blood oxygen level-dependent signals in bipolar disorder patients. However, fractal characteristics of brain blood oxygen level-dependent signals when responding to external emotional stimuli in pediatric bipolar disorder remain unclear. Blood oxygen level-dependent signals of 20 PBD-I patients and 17 age- and sex-matched healthy controls were extracted while performing an emotional Go-Nogo task. Neural responses relevant to the task and Hurst exponent of the blood oxygen level-dependent signals were assessed. Correlations between clinical indices and Hurst exponent were estimated. Significantly increased activations were found in regions covering the frontal lobe, parietal lobe, temporal lobe, insula, and subcortical nuclei in PBD-I patients compared to healthy controls in contrast of emotional versus neutral distractors. PBD-I patients exhibited higher Hurst exponent in regions that involved in action control, such as superior frontal gyrus, inferior frontal gyrus, inferior temporal gyrus, and insula, with Hurst exponent of frontal orbital gyrus correlated with onset age. The present study exhibited overactivation, increased self-similarity and decreased complexity in cortical regions during emotional Go-Nogo task in patients relative to healthy controls, which provides evidence of an altered emotional modulation of cognitive control in pediatric bipolar disorder patients. Hurst exponent may be a fractal biomarker of neural activity in pediatric bipolar disorder.
Assuntos
Transtorno Bipolar , Humanos , Criança , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/psicologia , Encéfalo/diagnóstico por imagem , Emoções/fisiologia , Lobo Frontal , Córtex Pré-Frontal , Mapeamento Encefálico , Imageamento por Ressonância MagnéticaRESUMO
Rafoxanide is commonly used as anti-helminthic medicine in veterinary medicine, a main compound of salicylanilide. Previous studies have reported that rafoxanide, as an inhibitor of BRAF V600E mutant protein, inhibits the growth of colorectal cancer, multiple myeloma, and skin cancer. However, its therapeutic effect on gastric cancer (GC) and the potential mechanism has not been investigated. Here, we have found that rafoxanide inhibited the proliferation of GC cells in vitro, arrested the cell cycle in the G0/G1 phase, and promoted apoptosis and autophagy in GC cells. Treatment with specific autophagy inhibitor 3-methyladenine drastically inhibited the apoptotic cell death effect by suppressing the switch from autophagy to apoptosis. Mechanistically, we found that rafoxanide inhibited the growth of GC cells in vitro by inhibiting the activity of the PI3K/Akt/mTOR signaling pathway. This process induced autophagy, which essentially resulted in the apoptosis of GC cells. Results from subcutaneous implanted tumor models in nude mice also indicated that rafoxanide inhibited the growth of GC cells in vivo. Taken together, our findings revealed that rafoxanide inhibited the growth of GC cells both in vitro and vivo, indicating a potential drug candidate for the treatment of GC.
Assuntos
Antineoplásicos/uso terapêutico , Antiplatelmínticos/uso terapêutico , Apoptose , Autofagia , Rafoxanida/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Antiplatelmínticos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Rafoxanida/farmacologia , Serina-Treonina Quinases TOR/metabolismoRESUMO
The expression of HS-1-associated protein X-1 (HAX-1) plays a major role in the development of hepatocellular carcinoma (HCC). However, the function of HAX-1 in HCC metastasis is unclear. Quantitative real-time PCR and western blotting were used to examine HAX-1 expression in HCC cell lines with different metastatic potential, and in tumor tissues with or without intrahepatic metastasis. HCC tissue arrays (nâ¯=â¯144) were used to assess correlations between clinicopathological parameters and HAX-1 expression. We also examined the effect of HAX-1 on promoting HCC cell metastasis in vivo and in vitro. The results showed that the expression levels of HAX-1 were higher in metastatic HCC cell lines than in non-metastatic HCC cell lines. HAX-1 was also significantly upregulated in primary HCC tissues with intrahepatic metastasis compared with those without intrahepatic metastasis. HCC in patients with high HAX-1 expression is more likely to metastasize. HAX-1 expression was associated with malignant progression and poor prognosis, and HAX1 silencing inhibited HCC cell migration and invasion in vitro and decreased HCC cell lung metastasis in vivo, whereas HAX-1 overexpression had the inverse effect. Moreover, HAX-1 increased HCC cell metastasis by promoting the epithelial-mesenchymal transition (EMT) process. Finally, we revealed that HAX-1 modulated EMT in HCC cells by increasing NF-κB/p65 nuclear translocation. In conclusion, HAX-1 promotes HCC metastasis by EMT through activating the NF-κB pathway, suggesting that HAX-1 could be a potential therapeutic target for HCC treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Metástase Neoplásica , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/secundário , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/secundário , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Prognóstico , Transdução de Sinais , Regulação para CimaRESUMO
BACKGROUND AND OBJECTIVES: Serine protease-3 (PRSS3) is a known contributor to the genesis and development of malignant tumors, although its role in gastric cancer (GC) is still unclear. METHODS: PRSS3 expression in GC tissue samples and its relationship with clinicopathological features were analyzed. Effects of GC cellular responses to the introduction of small interfering RNA (siRNA)-mediated and short hairpin RNA (shRNA)-mediated interference with tumor PRSS3 expression were also assessed. RESULTS: PRSS3 was significantly upregulated in GC tissues, and PRSS3 protein levels were higher in tumors that developed metastases soon after the surgery compared with those that remained metastasis-free. High expression of PRSS3 was associated with tumor N staging and independently predictive of postoperative prognosis in patients with GC. The V1 variant of PRSS3 was primarily detected in GC tissue and cell lines, the others (V2-V4) being scarcely detectable. Methylation and demethylation drugs had no impact on expression levels of any PRSS3 transcriptional variant. The downregulated PRSS3 expression suppressed GC cell growth, migration, and invasion in vitro and in vivo. CONCLUSIONS: PRSS3 appears to act as an oncogene of GC. High PRSS3 expression portends postoperative metastasis, serving as an effective biomarker of poor therapeutic outcomes.
Assuntos
Neoplasias Gástricas/enzimologia , Tripsina/biossíntese , Animais , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Processos de Crescimento Celular/fisiologia , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Transcrição Gênica , Tripsina/genéticaRESUMO
The tumor-suppressing role of fibulin-1 has been described in several types of cancers. However, the expression and role of fibulin-1 in the development and progression of gastric cancer (GC) remain largely unknown. In this study, RT-PCR and immunochemistry were used to detect the fibulin-1 expression in GC samples. We have found that the fibulin-1 protein and mRNA levels were downregulated in GC. When investigating the correlation between fibulin-1 expression and clinicopathological characteristics, we have found that low fibulin-1 protein expression was associated with poor tumor differentiation and advanced N stage. Low fibulin-1 protein expression was also an independent prognostic factor for patient survival. To clarify the reason of fibulin-1 downregulation in GC, the mRNA expression and methylation status of fibulin-1 were examined in GC fresh tissue samples (n = 36). We found that the transcriptional expression of fibulin-1 was negatively associated with fibulin-1 promoter hypermethylation, and fibulin-1 hypermethylation was associated with Helicobacter pylori infection. Finally, the effects of fibulin-1 overexpression on cell proliferation and apoptosis were examined. We have found that fibulin-1 overexpression suppressed the growth of GC both in vitro and in vivo and induced apoptosis by increasing cleaved caspase-3 expression. In conclusion, fibulin-1 acts as a tumor suppressor gene, is frequently hypermethylated in GC, and can potentially serve as a useful biomarker for patient prognosis.
Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias Gástricas/patologia , Animais , Apoptose , Biomarcadores Tumorais/genética , Western Blotting , Proteínas de Ligação ao Cálcio/genética , Proliferação de Células , Feminino , Citometria de Fluxo , Seguimentos , Genes Supressores de Tumor , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The tumor-suppressing role of Ras-association domain family 10 (RASSF10) has been described in several types of cancers. Here, we evaluated the potential use of the hypermethylation status of the RASSF10 promoter in serum as a new diagnostic and prognostic tool in gastric cancer (GC). We used bisulfite sequencing polymerase chain reaction to examine RASSF10 methylation levels in serum and/or tumor samples from 82 GC, 45 chronic atrophic gastritis (CAG), and 50 healthy control patients. In the serum of GC patients, the median level of RASSF10 methylation was higher at 47.84 % than those in the serum of CAG and healthy control patients at 11.89 and 11.35 %, respectively. The median level of RASSF10 methylation in GC tumor tissue was similarly high at 62.70 %. Furthermore, RASSF10 methylation levels were highly correlated between paired serum and tumor samples from GC patients. We performed receiver-operating characteristic curve analyses to verify that serum RASSF10 methylation levels could effectively distinguish GC from control patients. Moreover, multivariate analyses showed that high serum RASSF10 methylation levels in GC patients were associated with large tumors, lymph node metastasis, and high carcinoembryonic antigen (CEA) levels. Survival analyses showed that GC patients with high serum RASSF10 methylation levels had shorter overall and disease-free survival after D2 lymphadenectomy than those with low levels. High serum RASSF10 methylation levels were also an independent predictor of tumor recurrence and GC patient survival. In conclusion, serum RASSF10 promoter methylation levels can serve as a valuable indicator for the diagnosis and prognosis of GC in the clinic.
Assuntos
Biomarcadores Tumorais/sangue , Neoplasias Gástricas/diagnóstico , Proteínas Supressoras de Tumor/sangue , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Área Sob a Curva , Biomarcadores Tumorais/genética , Metilação de DNA , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas/genética , Curva ROC , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sensibilidade e Especificidade , Neoplasias Gástricas/sangue , Neoplasias Gástricas/genéticaRESUMO
Reactive astrocytosis has been considered either beneficial or detrimental effection in neuroinflammatory disease. HSPA12B, a new member belongs to the 70-kDa family of heat shock proteins (HSP70) which could modulate inflammatory response, also shows an connection with the astrocyte activation. Recently, it was reported that Src-Suppressed-C Kinase Substrate (SSeCKS) was detected in heat shock protein A12B (HSPA12B) interacting proteins using a yeast 2-hybrid system. SSeCKS, a major Lipopolysaccharide (LPS) response protein, has been involved in regulating astrocyte activation via production of proinflammatory factor in CNS inflammation. In this study, we found HSPA12B might regulate the expression and activity of SSeCKS to promote astrocyte inflammatory activation and release of inflammatory mediators, such as TNF-α and IL-1ß in spinal cord primary astroglial cultures exposed to LPS treatment. The promoting mechanism of interaction between HSPA12B and SSeCKS on LPS-induced astrocyte activation was mediated via the activation of JNK and p38 signaling pathways but not ERK1/2 MAPK signaling pathway. HSPA12B binded to SSeCKS via its both N terminus consisted of amino acids 1-330 and C terminus consisted of amino acids 1278-1596. And, in vivo, we confirmed the interaction between HSPA12B and SSeCKS of astrocyte activation in the pathogenesis of EAE. The regulatory mechanisms of HSPA12B-SSeCKS interaction may possibly be the key therapeutic strategy of neuroinflammatory disease.
Assuntos
Proteínas de Ancoragem à Quinase A/metabolismo , Astrócitos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Inflamação/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/imunologia , Células Cultivadas , Feminino , Cobaias , Células HEK293 , Humanos , Inflamação/imunologia , Lipopolissacarídeos/farmacologia , Ratos , Ratos Endogâmicos LewRESUMO
BACKGROUND: Remote ischemic conditioning (RIC) is an extremely simple, non-invasive, and cost-effective method with a neuroprotective effect. This study aimed to evaluate the immediate effects of one-time application of RIC on inflammation and coagulation in patients with chronic cerebral vascular stenosis, and compare the different effects of RIC on cerebral arteriostenosis and cerebral venostenosis. METHOD: A total of 47 patients with defined cerebral arteriostenosis (n=21) or venostenosis (n=26) were prospectively enrolled. RIC intervention was given once with 5 cycles of inflating and deflating for 5 minutes alternately. Blood was sampled 5 minutes before and after RIC for inflammatory and thrombophilia biomarkers. Differences in inflammatory and thrombotic variables at differing time points in the group were assessed using paired t tests or Wilcoxon matched-pairs signed-rank test. RESULTS: Patients with cerebral arteriostenosis had a higher level of pre-RIC neutrophil-to-lymphocyte ratio ( P =0.034), high-sensitivity C-reactive protein ( P =0.037), and fibrinogen ( P =0.002) than that with cerebral venostenosis. In the arterial group, levels of fibrinogen ( P =0.023) decreased, and interleukin-6 levels were elevated ( P =0.019) after a single RIC. Age was negatively related to interleukin-6, C-reactive protein, and fibrinogen. CONCLUSION: One-time RIC interventions may show seemingly coexisted proinflammatory and anti-coagulation effects of a single bout on patients with cerebral arteriostenosis. Older age was a negative predictor for multiple biomarkers in the cerebral arteriostensosis group. The protective effect of RIC on cerebral venostenosis patients needs to be further studied in a larger sample size.
Assuntos
Proteína C-Reativa , Interleucina-6 , Humanos , Biomarcadores , Anti-Inflamatórios , FibrinogênioRESUMO
The development of novel materials with effective defect-repairing properties will help avoid subtotal gastrectomy in patients with large gastric perforations. We prepared perfused decellularized gastric matrix (PDGM) and analyzed its components, spatial structure, biomechanics, cytotoxicity, and histocompatibility to validate its efficacy in the repair of gastric perforation. PDGM retained large amounts of gastric extracellular matrix, while residual glandular cells and muscle fibers were not found. The spatial structure of the tissue was well preserved, while the DNA and glycosaminoglycan contents were significantly decreased compared with normal gastric tissue (p < .01). There was no obvious deformation of the spatial structure and tissue elasticity of PDGM after sterilization by Cobalt-60 irradiation. The PDGM had good histocompatibility. PDGM was then used to repair a rat gastric perforation model. Radiography of the upper gastrointestinal tract at 24 hr postoperatively revealed no contrast agent leakage. There was evidence of early fibroblast proliferation, which was complicated by capillary regeneration. The hyperplastic gastric gland was slightly disarranged after repair. Defects of the muscular layer also healed a little with the regeneration process. PDGM is a nontoxic biocompatible biological mesh that may be useful for repairing relatively large gastric defects.
Assuntos
Materiais Biocompatíveis/química , Matriz Extracelular Descelularizada/química , Ruptura Gástrica/cirurgia , Estômago/química , Telas Cirúrgicas , Alicerces Teciduais/química , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Cerebral cortical vein thrombosis (CCVT) is often misdiagnosed because of its non-specific diagnostic symptoms. Here, we analyzed a cohort of patients with CCVT in hopes of improving understandings and treatments of the disease. A total of 23 patients with CCVT (confirmed with high-resolution imaging), who had been diagnosed between 2017 and 2019, were enrolled in this cohort study. Baseline demographics, clinical manifestations, laboratory data, radiological findings, treatment, and outcomes were collected and analyzed. Fourteen females and nine males were enrolled (mean age: 32.7 ± 11.9 years), presenting in the acute (within 7 days, n = 9), subacute (8-30 days, n = 7), and chronic (over 1 month, n = 7) stages. Headaches (65.2%) and seizures (39.1%) were the most common symptoms. Abnormally elevated plasma D-dimers were observed in the majority of acute stage patients (87.5%). The diagnostic accuracy of contrast-enhanced magnetic resonance venography (CE-MRV) and high-resolution magnetic resonance black-blood thrombus imaging (HR-MRBTI) in detecting CCVT were 57.1 and 100.0%, respectively. All patients had good functional outcomes after 6-month of standard anticoagulation (mRS 0-1) treatment. However, four CCVT patients that had cases involving multiple veins showed symptom relief after batroxobin therapy (p = 0.030). HR-MRBTI may be a fast and accurate tool for non-invasive CCVT diagnosis. HR-MRBTI combined with D-dimer can also precisely identify the pathological stage of CCVT. Batroxobin may safely accelerate cortical venous recanalization in combination with anticoagulation. Follow-up studies with larger sample sizes are suggested to evaluate the safety and efficacy of batroxobin for treating CCVT.
RESUMO
Bipolar disorder (BD) is clinically defined by alternating depressive and manic episodes with a separated period of euthymia. Thalamo-frontal loop plays vital role in psychotic symptoms, altered motor control and executive difficulties in BD. It remains unclear that structural and functional alterations of thalamo-frontal loop among the different mood states in BD, especially in pediatric BD(PBD).Twenty manic PBD (mPBD), 20 euthymic PBD (ePBD) and 19 healthy controls (HCs) were included in the study. By analyzing the T1 images and fMRI signals, thalamus volume and frontal grey matter cortical thickness were tested, and functional connectivity (FC) between bilateral thalamus and frontal cortex was calculated. Relationship between clinical indices and thalamo-frontal FC was also evaluated in mPBD and ePBD adolescents.Compared to HCs, the cortical thickness of left middle frontal gyrus (MFG), bilateral superior frontal gyrus (SFG) was significantly decreased in both mPBD and ePBD patients, and volume of left thalamus and cortical thickness of right MFG significantly decreased in mPBD patients. Compared to that of the HCs and ePBD subjects, thalamo-frontal hyperconnectivity with MFG was found in mPBD, and compared with that of HCs, thalamo-frontal hypoconnectivity with precentral gyrus/SFG was found in ePBD. In ePBD patients, episode times positively correlated with FC values between thalamus and precentral gyrus.The findings of the present study demonstrate detailed knowledge regarding shared and specific structural and functional disruption in thalamo-frontal loop in mPBD and ePBD subjects. Thalamo-frontal abnormalities reported in adult BD subjects were also observed in adolescent BD patients, and thalamo-frontal dysfunction may be a crucial treatment target in BD.
Assuntos
Transtorno Bipolar , Transtornos Psicóticos , Adolescente , Adulto , Transtorno Bipolar/diagnóstico por imagem , Criança , Humanos , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Tálamo/diagnóstico por imagemRESUMO
BACKGROUND: 3-Hydroxy butyrate dehydrogenase 2 (BDH2) is a short-chain dehydrogenase/reductase family member that plays a key role in the development and pathogenesis of human cancers. However, the role of BDH2 in gastric cancer (GC) remains largely unclear. Our study aimed to ascertain the regulatory mechanisms of BDH2 in GC, which could be used to develop new therapeutic strategies. METHODS: Western blotting, immunohistochemistry, and RT-PCR were used to investigate the expression of BDH2 in GC specimens and cell lines. Its correlation with the clinicopathological characteristics and prognosis of GC patients was analysed. Functional assays, such as CCK-8 and TUNEL assays, transmission electron microscopy, and an in vivo tumour growth assay, were performed to examine the proliferation, apoptosis, and autophagy of GC cells. Related molecular mechanisms were clarified by luciferase reporter, coimmunoprecipitation, and ubiquitination assays. RESULTS: BDH2 was markedly downregulated in GC tissues and cells, and the low expression of BDH2 was associated with poor survival of GC patients. Functionally, BDH2 overexpression significantly induced apoptosis and autophagy in vitro and in vivo. Mechanistically, BDH2 promoted Keap1 interaction with Nrf2 to increase the ubiquitination level of Nrf2. Ubiquitination/degradation of Nrf2 inhibited the activity of ARE to increase accumulation of reactive oxygen species (ROS), thereby inhibiting the phosphorylation levels of AktSer473 and mTORSer2448. CONCLUSIONS: Our study indicates that BDH2 is an important tumour suppressor in GC. BDH2 regulates intracellular ROS levels to mediate the PI3K/Akt/mTOR pathway through Keap1/Nrf2/ARE signalling, thereby inhibiting the growth of GC.
Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Hidroxibutirato Desidrogenase/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Neoplasias Gástricas/patologia , Ubiquitina/metabolismo , Animais , Apoptose , Autofagia , Biomarcadores Tumorais/genética , Movimento Celular , Proliferação de Células , Feminino , Humanos , Hidroxibutirato Desidrogenase/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Fator 2 Relacionado a NF-E2/genética , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas , Ubiquitinação , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The role of the human cervical cancer oncogene (HCCR-1) in the development of various tumors has been elucidated; however, its expression and function in gastric cancer remains largely unknown. Accordingly, the expression of HCCR-1 and epidermal growth factor (EGF) were detected in paired gastric cancer tissues and cell lines by western blotting (WB) and immunohistochemistry (IHC). Furthermore, the correlations between HCCR-1 expression in 209 gastric cancer tissues and the clinicopathological features and disease prognosis were analyzed. A stable HCCR-1 overexpression cell line was established, and the influence of increased HCCR-1 expression on the growth of gastric cancer cells was observed in vivo and in vitro. The expression of HCCR-1 generally increased in gastric cancer tissues. Further, increased HCCR-1 expression in gastric cancer tissues was associated with tumor T stage and was an independent factor that influenced poor postoperative prognosis in gastric cancer patients. A positive correlation was also detected between the expression of EGF and HCCR-1 in a time- and dose-dependent manner. The overexpression of HCCR-1 might enhance the growth rate of gastric cancer cells in vitro, increase the number of colony forming units, and promote the growth, volume, and weight of subcutaneous tumors in nude mice. In conclusion, HCCR-1 is a gastric cancer oncogene, and its increased expression plays a critical role in the occurrence and development of gastric cancer. Hence, HCCR-1 could serve as a valuable marker for the postoperative prognostic assessment of gastric cancer patients.
RESUMO
The RASSF10 has been identified as a tumor suppressor in human colorectal cancer (CRC). However, the expression of RASSF10 in patients with CRC has not been evaluated for its potential use as a biomarker in the diagnosis and prognosis assessment of CRC. We analyzed the expression of RASSF10 mRNA (n=30) and protein (n=205) in CRC and matched noncancerous colon tissue samples to explore the relationships among RASSF10 expression, clinicopathological factors, and prognosis in patients with CRC. Our results showed that the expression of RASSF10 mRNA and protein in CRC-adjacent tissues was higher than that in CRC tissues. Low RASSF10 expression was associated with the T stage (P=.037, odds ratio, 0.664; 95% confidence interval, 0.452-0.975) and the N stage (P<.001, odds ratio, 0.318; 95% confidence interval, 0.184-0.549) of the tumors. In addition, univariate analysis revealed that patients with CRC with lower RASSF10 expression had poorer overall survival (OS; P<.001) and disease-free survival (DFS; P<.001). The 5-year OS and DFS rates were 48.2% and 28.3%, respectively, in patients with low RASSF10 expression and 82.2% and 62.6%, respectively, in patients with high RASSF10 expression. Multivariate Cox regression analysis revealed that the strongest predictors of OS and DFS were RASSF10 expression (P<.001 and P<.001, respectively), T stage (P=.003 and P=.009, respectively), and N stage (P=.005 and P=.026, respectively). These results demonstrate that low expression of RASSF10 in CRC tissues is significantly correlated with poor survival after curative resection and may serve as a useful biomarker predictive of CRC prognosis.
Assuntos
Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , Proteínas Supressoras de Tumor/análise , Biomarcadores Tumorais/genética , Biópsia , Distribuição de Qui-Quadrado , Colectomia , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Regulação para Baixo , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , RNA Mensageiro/genética , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Proteínas Supressoras de Tumor/genéticaRESUMO
We developed a nanovector with double targeting properties for efficiently delivering the tumor suppressor gene RASSF1A specifically into hepatocellular carcinoma (HCC) cells by preparing galactosylated-carboxymethyl chitosan-magnetic iron oxide nanoparticles (Gal-CMCS-Fe3O4-NPs). After conjugating galactose and CMCS to the surface of Fe3O4-NPs, we observed that Gal-CMCS-Fe3O4-NPs were round with a relatively stable zeta potential of +6.5 mV and an mean hydrodynamic size of 40.1 ± 5.3 nm. Gal-CMCS-Fe3O4-NPs had strong DNA condensing power in pH 7 solution and were largely nontoxic. In vitro experiments demonstrated that Gal-CMCS-Fe3O4-NPs were highly selective for HCC cells and liver cells. In vivo experiments showed the specific accumulation of Gal-CMCS-Fe3O4-NPs in HCC tissue, especially with the aid of an external magnetic field. Nude mice with orthotopically transplanted HCC received an intravenous injection of the Gal-CMCS-Fe3O4-NPs/pcDNA3.1(+)RASSF1A compound and intraperitoneal injection of mitomycin and had an external magnetic field applied to the tumor area. These mice had the smallest tumors, largest percentage of TUNEL-positive cells, and highest caspase-3 expression levels in tumor tissue compared to other groups of treated mice. These results suggest the potential application of Gal-CMCS-Fe3O4-NPs for RASSF1A gene delivery for the treatment of HCC.
Assuntos
Receptor de Asialoglicoproteína/metabolismo , Carcinoma Hepatocelular/terapia , Quitosana/análogos & derivados , Técnicas de Transferência de Genes , Terapia Genética/métodos , Neoplasias Hepáticas/terapia , Proteínas Supressoras de Tumor/genética , Animais , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Quitosana/farmacologia , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Transplante Heterólogo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/uso terapêuticoRESUMO
Methylation of the Ras-association domain family 10 (RASSF10) promoter region correlates with clinicopathological characteristics and poor prognosis in several human cancers. Here, we examined RASSF10 expression in hepatocellular carcinoma (HCC) and its role in hepatocarcinogenesis. RASSF10 mRNA and protein levels were downregulated in both HCC cell lines and patient tissue samples. In patient tissues, low RASSF10 levels correlated with hepatocirrhosis, poor tumor differentiation, tumor thrombus and Barcelona Clinic Liver Cancer stage, and were indicative of increased tumor recurrence and reduced patient survival. Low RASSF10 expression was associated with promoter hypermethylation, which was in turn associated with polycyclic aromatic hydrocarbon and aflatoxin B1 exposure, but not DNA methyltransferase expression. Overexpression of RASSF10 in HCC cell lines suppressed cell growth and colony formation, and induced apoptosis by up- or down-regulating specific Bcl-2 family proteins. RASSF10 overexpression increased pro-apoptotic Bax and Bad levels, but decreased anti-apoptotic Bcl-2 and Bcl-xl expression. Overexpression also inhibited tumor formation in nude mice and reduced cell migration and invasion by inhibiting the epithelial-mesenchymal transition. RASSF10 knockdown promoted cell growth. Our results show that RASSF10 is frequently hypermethylated and down-regulated in HCC and can potentially serve as a useful biomarker predictive of HCC patient prognosis.