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Maintaining genomic stability is a prerequisite for proliferating NPCs to ensure genetic fidelity. Though histone arginine methylation has been shown to play important roles in safeguarding genomic stability, the underlying mechanism during brain development is not fully understood. Protein arginine N-methyltransferase 5 (PRMT5) is a type II protein arginine methyltransferase that plays a role in transcriptional regulation. Here, we identify PRMT5 as a key regulator of DNA repair in response to double-strand breaks (DSBs) during NPC proliferation. Prmt5F/F; Emx1-Cre (cKO-Emx1) mice show a distinctive microcephaly phenotype, with partial loss of the dorsal medial cerebral cortex and complete loss of the corpus callosum and hippocampus. This phenotype is resulted from DSBs accumulation in the medial dorsal cortex followed by cell apoptosis. Both RNA sequencing and in vitro DNA repair analyses reveal that PRMT5 is required for DNA homologous recombination (HR) repair. PRMT5 specifically catalyzes H3R2me2s in proliferating NPCs in the developing mouse brain to enhance HR-related gene expression during DNA repair. Finally, overexpression of BRCA1 significantly rescues DSBs accumulation and cell apoptosis in PRMT5-deficient NSCs. Taken together, our results show that PRMT5 maintains genomic stability by regulating histone arginine methylation in proliferating NPCs.
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Células-Tronco Neurais , Reparo de DNA por Recombinação , Animais , Camundongos , Arginina/metabolismo , Reparo do DNA , Instabilidade Genômica , Genômica , Histonas/genética , Histonas/metabolismo , Células-Tronco Neurais/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismoRESUMO
OBJECTIVE: The aim of the study is to investigate the value of computed tomography (CT) radiomics features to discriminate the liver metastases (LMs) of digestive system neuroendocrine tumors (NETs) from neuroendocrine carcinoma (NECs). METHODS: Ninety-nine patients with LMs of digestive system neuroendocrine neoplasms from 2 institutions were included. Radiomics features were extracted from the portal venous phase CT images by the Pyradiomics and then selected by using the t test, Pearson correlation analysis, and least absolute shrinkage and selection operator method. The radiomics score (Rad score) for each patient was constructed by linear combination of the selected radiomics features. The radiological model was constructed by radiological features using the multivariable logistic regression. Then, the combined model was constructed by combining Rad score and the radiological model into logistic regression. The performance of all models was evaluated by the receiver operating characteristic curves with the area under curve (AUC). RESULTS: In the radiological model, only the enhancement degree (odds ratio, 8.299; 95% confidence interval, 2.070-32.703; P = 0.003) was an independent predictor for discriminating the LMs of digestive system NETs from those of NECs. The combined model constructed by the Rad score in combination with the enhancement degree showed good discrimination performance, with AUCs of 0.893, 0.841, and 0.740 in the training, testing, and external validation groups, respectively. In addition, it performed better than radiological model in the training and testing groups (AUC, 0.893 vs 0.726; AUC, 0.841 vs 0.621). CONCLUSIONS: The CT radiomics might be useful for discrimination LMs of digestive system NECs from NETs.
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Carcinoma Neuroendócrino , Neoplasias Hepáticas , Tumores Neuroendócrinos , Humanos , Tumores Neuroendócrinos/diagnóstico por imagem , Carcinoma Neuroendócrino/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Neoplasias Hepáticas/diagnóstico por imagem , Sistema Digestório , Estudos RetrospectivosRESUMO
miR-200c-3p is aberrantly expressed in numerous cancers, but its underlying mechanisms in nephroblastoma are unknown. In our study, the differentially regulated miRNAs between the nephroblastoma tissues and adjacent non-neoplastic renal tissues were screened based on microarray analysis. The miR-200c-3p expression in nephroblastoma tissues and cells was detected by qRT-PCR. Then, the effects of miR-200c-3p mimic or inhibitor on cell proliferation, invasion, and migration were evaluated by CCK-8 assay, plate colony formation assay, soft agar assay, Transwell, and wound-healing assay in SK-NEP-1 and G401 cells. Afterward, the target gene of miR-200c-3p was predicted by TarBase, miRTarBase, miRDB softwares, and then verified by dual-luciferase reporter gene assay. The in vivo effects of miR-200c-3p on pathological changes and tumor volume were investigated in tumor xenograft mice by H&E staining and in vivo fluorescence imaging. ChIP assay was used to evaluate the relationship between histone acetyltransferase E1A-binding protein p300 (EP300) and P27, and the relationship of the role of miR-200c-3p in nephroblastoma and the AKT/FOXO1/p27 signaling pathways was evaluated by western blotting. Our study shows that miR-200c-3p was downregulated in nephroblastoma tissues and cells, and EP300 was a target gene of miR-200c-3p. Furthermore, miR-200c-3p mimic decreased cell proliferation and inhibited cell migration and invasion in nephroblastoma. Mechanistically, miR-200c-3p could inhibit p-AKT activity and enhance p-FOXO1 and p27 expression. Notably, the transcription factor P27 could bind to the EP300 promoter. This study demonstrates a new approach to treat nephroblastoma.
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It has been reported that Netrin-1 is involved in neuroprotection following injury to the central nervous system. However, the minimal functional domain of Netrin-1 which can preserve the neuroprotection but avoid the major side effects of Netrin remains elusive. Here, we investigated the neuroprotective effect of a peptide E1 derived from Netrin-1's EGF3 domain (residues 407-422). We found that it interacts with deleted colorectal carcinoma (DCC) to activate focal adhesion kinase phosphorylation exhibiting neuroprotection. The administration of the peptide E1 was able to improve functional recovery through reduced apoptosis in an experimental murine model of intracerebral hemorrhage (ICH). In summary, we reveal a functional sequence of Netrin-1 that is involved in the recovery process after ICH and identify a candidate peptide for the treatment of ICH.
Assuntos
Morte Celular/efeitos dos fármacos , Hemorragia Cerebral/tratamento farmacológico , Netrina-1/metabolismo , Netrina-1/farmacologia , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose , Comportamento Animal , Sobrevivência Celular , Receptor DCC/genética , Modelos Animais de Doenças , Proteína-Tirosina Quinases de Adesão Focal , Células HEK293 , Humanos , Camundongos , Netrina-1/genéticaRESUMO
BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) is poor, with 60% to 70% of patients developing recurrence and metastasis within five years of radical resection. Alpha-fetoprotein (AFP) plays a significant role in predicting the recurrence and metastasis of HCC after surgery. However, its role in modulating tumor immunity has not been investigated. Our objective was to examine the effect of AFP on the expression of B7 family and activation of the NF-κB (P65) pathway in HCC. METHODS: We generated human hepatoma SMMC-7721 cell lines with or without recombinant AFP transfection (AFPup and control groups). Colony formation assay, Transwell invasion assay, and wound healing assay were used to detect the function of AFP. Liver cancer xenografts were made in BALB/c nude male mice (N = 6 per group). After 28 days of inoculation, the expression of immune genes in the HCC tissues, including PD-L (B7-H1), B7-H3, B7-H4, and P65, was evaluated by quantitative real-time PCR (qPCR) and western blot. In addition, immunofluorescence was used to determine the subcellular localization of the P65 protein, a key factor in the NF-κB pathway. An online HCC patients' dataset was also used to detect the connection between AFP and P65. RESULTS: Overexpression of AFP could enhance proliferation, invasion, and migration of HCC cells. Both qPCR and western blot results demonstrated that the expressions of PD-L1, B7-H4, and P65 were significantly higher in the AFP group compared to the controls (P < 0.05). Immunofluorescence results indicated that the majority of the P65 protein was located in the cytoplasm in the control group but was translocated to the nucleus in the AFPup group. The Spearman correlation coefficient confirms that AFP has a positive correlation with P65 in HCC patients (R = 0.33, P=0.05). CONCLUSION: AFP could enhance proliferation, invasion, and migration in HCC cells. The upregulation of AFP would increase the PD-L1 and B7-H4 mRNA and protein expression in HCC tissues through the upregulation and activation of the P65 protein.
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Objective: Cancer is expected to be the leading cause of death worldwide within the 21st century and is the single most important obstacle to extending life expectancy. Unfortunately, the most effective approach to combating cancers remains a complex and unsolved problem. Siglec-15 is a member of the Siglec family and plays a conserved regulatory role in the immune system of vertebrates. Previous studies on Siglec-15 have focused on its function in osteoclast regulation. The purpose of this study was to explore the significance of Siglec-15 mRNA in human cancer mainly based on information obtained from online databases. Method: Data were collected from several online databases. Serial analysis of gene expression (SAGE) and Virtual Northern, UALCAN Database Analysis, Catalog of Somatic Mutations in Cancer (COSMIC) analysis, the cBio cancer genomics portal, Cancer Regulome tools and data, Kaplan-Meier Plotter Analysis and the UCSC Xena website were used to analyze the data. Results: Compared with normal tissues, Siglec-15 up-regulation was widely observed in tuomrs. Differences in Siglec-15 expression were associated with different prognoses. Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types. Conclusion: Siglec-15 is a potential target for the expansion of cancer immunotherapy.
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Neocortex development during embryonic stages requires the precise control of mRNA metabolism. Human antigen R (HuR) is a well-studied mRNA-binding protein that regulates mRNA metabolism, and it is highly expressed in the neocortex during developmental stages. Deletion of HuR does not impair neural progenitor cell proliferation or differentiation, but it disturbs the laminar structure of the neocortex. We report that HuR is expressed in postmitotic projection neurons during mouse brain development. Specifically, depletion of HuR in these neurons led to a mislocalization of CDP+ neurons in deeper layers of the cortex. Time-lapse microscopy showed that HuR was required for the promotion of cell motility in migrating neurons. PCR array identified profilin 1 (Pfn1) mRNA as a major binding partner of HuR in neurons. HuR positively mediated the stability of Pfn1 mRNA and influenced actin polymerization. Overexpression of Pfn1 successfully rescued the migration defects of HuR-deleted neurons. Our data reveal a post-transcriptional mechanism that maintains actin dynamics during neuronal migration.
Assuntos
Movimento Celular , Proteína Semelhante a ELAV 1/fisiologia , Neurônios/fisiologia , RNA Mensageiro/metabolismo , Animais , Padronização Corporal/genética , Movimento Celular/genética , Células Cultivadas , Embrião de Mamíferos , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/fisiologia , Neurogênese/genética , Gravidez , Profilinas/fisiologia , Processamento Pós-Transcricional do RNA/genéticaRESUMO
Hepatocellular Carcinoma (HCC) is one of the most common malignancies in the world, and is well-known for its bad prognosis. Potassium calcium-activated channel subfamily N member 4 (KCNN4) is a type of intermediate conductance calcium-activated potassium channel, and increasing evidence suggests that KCNN4 contributes to the regulation of invasion and metastasis in a number of cancers. However, its clinical significance and biological function remain unclear in the HCC disease process. In this study, the expression levels of KCNN4 in 86 HCC samples were compared with corresponding paracancerous tissues. sh-RNA was used to reduce the expression of KCNN4 in Hep3B HCC cells in vitro; this was confirmed by Real time-PCR and western blotting. Wound healing, transwell assays and high content analysis were performed to investigate the tumor-promoting characteristics of KCNN4 in Hep3B HCC cells. As results, KCNN4 expression was significantly associated with preoperative serum alpha-fetoprotein level (p=0.038) and TNM stage (p=0.039). Additionally, patients with high KCNN4 amplification in HCC tissue exhibited shorter disease-free survival, whereas there was no statistical significance between KCNN4 amplification and overall survival. Wound healing and transwell assays showed that knockdown of KCNN4 expression could reduce migration and invasion abilities of HCC cells. High content analysis result showed that down-regulated KCNN4 could inhibit the ability of HCC cell proliferation. The mitogen-activated protein kinase (MAPK) pathway is active in cell proliferation, differentiation, migration, senescence, and apoptosis. Matrix metallopeptidase 9 and extracellular signal regulated kinase 1/2 (ERK1/2) were important biomarkers of MAPK/ERK pathway, knockdown of KCNN4 reduced the expression of MMP9 and ERK1/2. These findings showed that KCNN4 promotes HCC invasion and metastasis through the MAPK/ERK pathway.
Assuntos
Carcinoma Hepatocelular/metabolismo , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Neoplasias Hepáticas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/fisiopatologia , Metástase Neoplásica/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Análise Serial de TecidosRESUMO
BACKGROUND: This study aims to provide guidance for clinical work through analysis of the clinical characteristics, endoscopic and pathological manifestations, diagnosis, and treatment of an 18-day-old neonate with exfoliative esophagitis. CASE PRESENTATION: The patient presented with vomiting but the parents did not pay too much attention. The pathological report revealed numerous fibrinous exudative necrotic, and inflammatory cells, as well as a small amount of squamous epithelium. Furthermore, milk allergy factors were considered. Conservative treatments, such as fasting, acid suppression, mucosal protection, parenteral nutrition, and the replacement of anti-allergic milk powder were given. Thereafter, endoscopic examination revealed that the patient returned to normal, and was discharged after 21 days. CONCLUSIONS: Exfoliative esophagitis has multiple causes; and has characteristic clinical and endoscopic manifestations. Endoscopic examination after 18 days presentation and conservative therapy revealed that the esophagus had returned to a normal appearance and the patient was discharged. Following discharge, the parents were advised to feed the patient ALFERE powder. Attention should be given to the timely detection of complications and corresponding treatment.
Assuntos
Mucosa Esofágica/patologia , Esofagite/patologia , Proteína C-Reativa/análise , Epitélio/patologia , Esofagite/sangue , Esofagite/complicações , Esofagoscopia , Humanos , Recém-Nascido , Lábio/patologia , Doenças Labiais/complicações , Doenças Labiais/patologia , Masculino , Vômito/etiologiaRESUMO
To increase the detection rate of deep vein thrombosis (DVT) and to compare the predictive value of four different risk assessment scales (Caprini, Autar, Pauda, and Khorana scales) for DVT in patients with solid tumors by the receiver operating curve (ROC). A total of 361 patients with all kinds of malignant solid tumors, who accepted anti-tumor therapy in the cancer center between March 3, 2015 to April 13, 2018, were assigned to a group of 230 cases diagnosed with DVT and a control group of 131 cases without DVT. Data were recorded and summarized, and the predictive value of the above four risk assessment scales for DVT in solid tumor patients was compared based on the area under the ROC curve (AUC). The AUC values determined for the Caprini, Autar, Pauda, and Khorana scales were (0.631 ± 0.030), (0.686 ± 0.028), (0.654 ± 0.029), and (0.599 ± 0.032), respectively; maximum sensitivity, specificity, and Youden index were 80.9% for Khorana, 86.3% for Caprini, and 29.6% for Autar scale, respectively. We found no statistically significant differences in the AUC values between Autar and Caprini, Autar and Khorana, as well as Khorana and Pauda (p > 0.05). However, the AUC differences between Autar and Pauda, Caprini and Khorana, as well as Caprini and Pauda were statistically significant (p < 0.05). All four risk assessment models showed some value in the risk prediction of DVT in patients with solid tumors, but every model also exhibited its own restrictions; maximum sensitivity, specificity, and Youden index were 80.9% for Khorana, 86.3% for Caprini, and 29.6% for Autar scale, respectively. We confirmed that the detection rate can be improved by modifying the BMI cut-off value of the scale or by combining appropriate scales.
Assuntos
Neoplasias/complicações , Medição de Risco/métodos , Trombose Venosa/etiologia , Idoso , Índice de Massa Corporal , Estudos de Casos e Controles , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Curva ROC , Estudos Retrospectivos , Medição de Risco/normas , Sensibilidade e EspecificidadeRESUMO
Circadian clock genes have become a hot topic in cancer research in recent years, and more and more studies are showing that clock genes are involved in regulating cell proliferation cycle and apoptosis of malignant tumors, neuroendocrine and immune function, and other processes. Lung cancer is a malignant tumor with increasing incidence worldwide. The pathogenesis of lung cancer is extremely complicated and includes genetic factors, living environment, and smoking, and the occurrence of lung cancer is related to the regulation of many oncogenes and tumor suppressor genes. But there are few studies on clock genes in lung cancer. Studies on clock genes may help to better understand the mechanism of lung cancer development for an improved treatment. The expressions of all 14 kinds of clock genes in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), two main kinds of non-small-cell lung cancer (NSCLC), were studied based on integration and analysis of data from The Cancer Genome Atlas (TCGA) to show the association between clock gene expression and prognosis of cancer patients. Analysis of TCGA data indicated that overexpression of Cry2, BMAL1, and RORA with underexpression of Timeless and NPAS2 was associated with a favorable prognosis of ADC, and the expression of NPAS2 was associated with the time of patient survival. Additionally, the expression of Cry2 was related to TNM stage. In SCC, high expression of DEC1 was correlated with poor overall survival in patients and the expression of Timeless was associated with the time of patient survival. In NSCLC, circadian clock genes constitute cancer circadian rhythm by interacting with each other, showing that asynchrony with normal tissues, which collectively controlling the occurrence and development of NSCLC.
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Carcinoma Pulmonar de Células não Pequenas/genética , Relógios Circadianos/fisiologia , Ritmo Circadiano/genética , Neoplasias Pulmonares/genética , Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma de Células Escamosas/genética , Expressão Gênica/genética , Humanos , PrognósticoRESUMO
Circadian rhythm describes the 24-h oscillation in physiology and behavior of living organisms and presents a timing controller for life activity. Studies in recent years have reported that the abnormal expression of clock genes is closely related to the development of common abdominal malignant tumors. The expression of the 14 kinds of clock genes in 6 abdominal malignant tumors from Cancer Genome Atlas (TCGA) data was integrated and analyzed using R and Perl programming languages to show the association between clock gene expression and prognosis of cancer patients. Analysis of TCGA data indicated that the overexpression of Per1-3, Cry2, CLOCK, NR1D2 and RORA with underexpression of Timeless and NPAS2 was associated with a favorable prognosis in kidney cancer. In liver cancer, high expressions of Cry2 and RORA were correlated with prolonged overall survival (OS) in patients, while high expressions of NPAS2 and Timeless were correlated with a poor survival. High expression of CLOCK was positively correlated with OS in colon cancer patients. High expression of Cry2 and low expression of DEC1 were associated with a favorable prognosis in pancreatic cancer patients, respectively. Most of these clock-genes expressions were closely related to the clinical stage and degree of tumor differentiation of patients. Aberrant clock gene expression is related to the biological characteristics of abdominal malignant tumors, which likely has a causal role in cancer development and survival.
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Neoplasias Abdominais/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criptocromos/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas do Tecido Nervoso/genética , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Oscilometria , Proteínas Circadianas Period/genética , PrognósticoRESUMO
Chronic stress has been observed to increase the risk of developing depression and induce neuronal alterations of synaptic plasticity, yet the underlying molecular mechanisms remain unclear. Here, we found that the ubiquitously expressed RNA-binding protein HuR was up-regulated in the medial prefrontal cortex (mPFC) of mice following chronic stress. In adult mice, AAV-Cre-mediated knockout of HuR in the mPFC prevented anxiety-like and depression-like behaviors induced by chronic stress. HuR was also required for the stress-induced dendritic spine loss and synaptic transmission deficits. Moreover, HuRflox/flox;Nex-Cre mice, which induce HuR loss of function from embryonic development, exhibited enhanced synaptic functions. Notably, we ascertained RhoA signaling to be regulated by HuR and involved in the modulation of structural synaptic plasticity in response to chronic stress. Our results demonstrate HuR is a critical modulator for the regulation of stress-induced synaptic plasticity alterations and depression, providing a potential therapeutic target for the treatment of depressive disorders.
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Depressão/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Plasticidade Neuronal/fisiologia , Córtex Pré-Frontal/metabolismo , Animais , Depressão/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Restrição Física , Estresse Psicológico/complicaçõesRESUMO
PURPOSE: The objective of this study was to analyze the clinical features and prognosis of gastroenteropancreatic (GEP) neuroendocrine carcinomas (NECs) with liver metastasis and primary hepatic neuroendocrine carcinomas (PHNECs), as these rare hepatic neuroendocrine carcinomas have not been exhaustively studied. METHODS: The clinical data of 47 patients with hepatic NECs were retrospectively reviewed and categorized to analyze features and prognosis. RESULTS: The 47 studied cases comprised 13 cases of primary hepatic NECs (primary group) and 34 cases of metastatic hepatic NECs (metastatic group). Male patients were slightly dominant in both groups, while no age predilection was present. PHNECs were mostly single nodules located in the right lobe of the liver. Metastatic hepatic NECs originated mostly from the pancreas and stomach without distinction of the lobes of the liver. Univariate analysis showed that the treatment protocol (radical operation or others) was correlated with the overall survival (OS; p < 0.05) in the primary group, while treatment protocol and cytokeratin 7 (CK7) were associated with OS (p < 0.05) in the metastatic group. Cox proportional hazard regression showed that radical operation was an independent prognostic factor (p < 0.05) for OS in the metastatic group. CONCLUSIONS: No significant differences in the clinicopathological features between PHNECs and metastatic hepatic GEP NECs were found, but radical operation was significantly correlated with OS for both carcinomas. Radical operation is the first choice for patients who are eligible for operation.
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Carcinoma Neuroendócrino/patologia , Neoplasias Intestinais/patologia , Neoplasias Hepáticas/patologia , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/patologia , Nódulo Pulmonar Solitário/patologia , Neoplasias Gástricas/patologia , Adulto , Idoso , Carcinoma Neuroendócrino/cirurgia , Feminino , Humanos , Neoplasias Intestinais/cirurgia , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Estudos Retrospectivos , Nódulo Pulmonar Solitário/cirurgia , Neoplasias Gástricas/cirurgia , Análise de SobrevidaRESUMO
To investigate the effect of multi-kinase kinase inhibitors (sorafenib; regorafenib; lenvatinib) on the invasion and metastasis of human hepatocellular carcinoma (HCC) cells, and the outcome of this effect on the expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), yet unclarified. Cells were subjected to four different treatments: blank control group, sorafenib (10⯵mol/L) treatment group, regorafenib (20â¯mmol/L) treatment group, and lenvatinib (4⯵mol/L) treatment group. Anti-invasion and anti-metastasis effects were tested using the wound-healing assay and transwell invasion assay. Real-time PCR and Western blot analyses were used to determine the impact of sorafenib, regorafenib, and lenvatinib on the gene expression of MMPs and TIMPs in the two HCC lines (Hep3B and SMMC-7721). Results from the wound-healing and transwell invasion assays showed the three tested anti-cancer drugs to have a significant inhibitory effect on the metastasis and invasion of HCC cells. Real-time PCR and western blot analyses revealed that sorafenib down-regulated the expressions of MMP-7,10,16 and up-regulated those of TIMP-1,3,4, regorafenib down-regulated the expression of MMP-1 and up-regulated TIMP-3 gene expression, and lenvatinib down-regulated the expressions of MMP-1,2,7,9,10,16 and up-regulated those of TIMP-1,3,4. However, these three targeted anti-cancer drugs seem to have no significant regulatory effect on the expressions of other MMPs and TIMPs family genes. In conclusion, sorafenib, regorafenib, and lenvatinib inhibit the invasion and metastasis of HCC cells by regulating MMPs/TIMPs expression levels.
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Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Metaloproteinases da Matriz/genética , Inibidores Teciduais de Metaloproteinases/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Metaloproteinases da Matriz/metabolismo , Terapia de Alvo Molecular/métodos , Família Multigênica , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Quinolinas/farmacologia , Sorafenibe/farmacologia , Inibidores Teciduais de Metaloproteinases/metabolismoRESUMO
Neuroendocrine tumors (NETs) of the gastrointestinal tract often spread to the liver, while primary hepatic NETs (PHNETs), first described by Edmondson in 1958, are very rare. The majority of existing reports regarding PHNETs have small sample sizes, and the clinicopathological characteristics and prognostic factors are still unclear. The aim of the present study was to analyze the clinicopathological features and explore the prognostic factors of PHNETs. From March 2012 to March 2017, 28 cases of PHNETs were retrospectively evaluated to analyze the clinicopathological features and explore the prognostic factors of PHNETs. The 28 PHNETs patients were males (n=15) and females (n=13) aged between 32 and 76 years (mean=53 years). Among them, 16 patients had clinical symptoms. The remaining 12 patients had no obvious clinical symptoms, only hepatoncus was observed during physical examination. Single-factor analysis showed that carbohydrate antigen 125 (CA125), alanine aminotransferase (ALT), aspartate aminotransferase (AST), hemoglobin (HB), Ki-67 positive index (PI), surgical treatment and pathological grading were correlated to PHNET prognosis (P<0.05); multifactor analysis revealed that Ki-67 PI was associated with the prognosis (P<0.05). Thus, the prognosis of PHNETs may be effectively predicted using the indexes of CA125, ALT, AST, HB, Ki-67 PI, pathological grading and surgical treatment. Pathological classification of grade 3, high expression of Ki-67 PI, abnormal elevation of CA125, abnormalities of ALT and AST, anemia and lack of radical operation indicated a poor prognosis. High expression of Ki-67 PI was an independent prognostic factor for PHNETs.
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BACKGROUND: The molecular mechanisms involved in the development and metastasis of hepatocellular carcinoma (HCC) are complex. Molecule-targeted drugs are characterized by strong specificity and low toxicity, but the clinical research of these drugs still exhibits many difficulties, such as poor target specificity. With the in-depth study of the tumor immunological theory, therapies based on overcoming the tumor immune escape to produce a specific effective tumor immune response has gradually become a hot topic in tumor research. We hope that by studying the effects of liver-targeted drugs on the expression of immune-related proteins in hepatocellular carcinoma cells, we will find a potential link to further guide the clinical drug use. METHODS: Human hepatoma Hep3B cells were used to establish liver cancer xenografts by inoculating 40 BALB/c nude mice. The following five groups of mice (8 mice per group) were randomly set up: lenvatinib group, apatinib group, sorafenib group, regorafenib group, and dimethyl sulfoxide (DMSO) group. After treatment, we analyzed PD-L1 and B7-H3 mRNA using the real-time polymerase chain reaction (PCR) assay and assessed the PD-L1 and B7-H3 protein expression by Western immunoblotting. RESULTS: Real-time PCR results suggested that the mRNA expression of PD-L1 in the lenvatinib group was significantly higher than that in the control group, while its expression in the regorafenib group was significantly lower than that in the control group (both pâ¯<â¯.05). Western immunoblotting results suggested that, compared with the control group, PD-L1 protein was increased in the lenvatinib group, while its expression in the regorafenib group was decreased. CONCLUSION: Lenvatinib and regorafenib affected the expression of PD-L1 in the process of anti-HCC.
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Antineoplásicos/farmacologia , Antígenos B7/antagonistas & inibidores , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas Experimentais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Animais , Antígenos B7/biossíntese , Antígenos B7/imunologia , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/patologia , Humanos , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/imunologia , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Mensageiro/antagonistas & inibidores , RNA Mensageiro/biossíntese , RNA Mensageiro/imunologiaRESUMO
BACKGROUND: Neuroendocrine tumors (NETs) are uncommon type of cancers, also known as APUD (amine precursor uptake decarboxylation) tumors, which are becoming increasingly prevalent. Alkaline phosphatase (ALP) is a poor prognosis factor in a number of hepatic diseases. However, its distribution and prognostic value in primary hepatic neuroendocrine tumors (PHNETs) are still not clear. In this study, our aim is to investigate the correlations between ALP and clinicopathological features and prognostic factors of PHNETs. METHODS: The clinical data of 22 patients with PHNETs were retrospectively reviewed to investigate whether ALP affects the prognosis of PHNETs. RESULTS: In this study, ALP is correlated to γ-glutamyl transpeptidase (GGT; pâ¯=â¯0.002) and the tumor location in the liver (pâ¯=â¯0.007), and increased levels of ALP had poor effects on overall survival (pâ¯=â¯0.006) and progression-free survival (pâ¯=â¯0.022). CONCLUSION: ALP was identified as an independent prognostic factor for overall survival of PHNETs.
Assuntos
Fosfatase Alcalina/metabolismo , Tumores Neuroendócrinos/diagnóstico , Tumores Neuroendócrinos/enzimologia , gama-Glutamiltransferase/metabolismo , Feminino , Humanos , Masculino , Análise de SobrevidaRESUMO
Newborn neurons undergo inside-out migration to their final destinations during neocortical development. Reelin-induced tyrosine phosphorylation of disabled 1 (Dab1) is a critical mechanism controlling cortical neuron migration. However, the roles of Reelin-independent phosphorylation of Dab1 remain unclear. Here, we report that deleted in colorectal carcinoma (DCC) interacts with Dab1 via its P3 domain. Netrin 1, a DCC ligand, induces Dab1 phosphorylation at Y220 and Y232. Interestingly, knockdown of DCC or truncation of its P3 domain dramatically delays neuronal migration and impairs the multipolar-to-bipolar transition of migrating neurons. Notably, the migration delay and morphological transition defects are rescued by the expression of a phospho-mimetic Dab1 or a constitutively active form of Fyn proto-oncogene (Fyn), a member of the Src-family tyrosine kinases that effectively induces Dab1 phosphorylation. Collectively, these findings illustrate a DCC-Dab1 interaction that ensures proper neuronal migration during neocortical development.
Assuntos
Receptor DCC/metabolismo , Neocórtex/crescimento & desenvolvimento , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Animais , Animais Recém-Nascidos , Movimento Celular/fisiologia , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/citologia , Neocórtex/metabolismo , Netrina-1/metabolismo , Fosforilação , Domínios Proteicos , Proto-Oncogene Mas , Proteína ReelinaRESUMO
Single-chain variable fragment (scFv) antibodies are the smallest immunoglobulins with high antigen-binding affinity. We have previously reported that fibroblast growth factor 1 played pivotal roles in cancer development and generated a mouse scFv (mscFv1C9) could effectively prohibit cancer cell proliferation in vitro and in vivo. Here, we further humanized this scFv (hscFv1C9) using a structure-guided complementarity determining region grafting strategy. The purified hscFv1C9 maintained similar antigen-binding affinity and specificity as mscFv1C9, and it was capable of inhibiting growth of different tumours in vitro and in vivo. These data strongly suggested that hscFv1C9 has antitumour potentials.