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1.
Technol Cancer Res Treat ; 19: 1533033820905825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32216582

RESUMO

MicroRNAs are known to be important in a variety of cancer types. The specific expression and roles of miR-338-3p in the context of gastric cancer, however, remains largely unknown. In this study, we found that miR-338-3p was expressed significantly lower in established/primary human gastric cancer cells than that in human gastric epithelial cells; miR-338-3p is also decreased in human gastric cancer tissues and was positively associated with the worse prognosis of patients with gastric cancer. Enforced expression of miR-338-3p could inhibit cell growth, survival, and proliferation, while inducing cell apoptosis. In addition, miR-338-3p negatively regulated SOX5 expression through directly binding to the 3'-untranslated region of SOX5, and an inverse correlation was found between miR-338-3p and SOX5 messenger RNA expression in gastric cancer tissues. Furthermore, miR-338-3p-induced inactivation of Wnt/ß-catenin signaling was greatly abrogated by SOX5 upregulation. Finally, we found that hypoxic conditions were linked with reduced miR-338-3p expression in the context of gastric cancer. In conclusion, miR-338-3p acts as a tumor suppressor in gastric cancer, possibly by directly targeting SOX5 and blocking Wnt/ß-catenin signaling. These findings might provide novel therapeutic targets for gastric cancer.

2.
Horm Cancer ; 10(4-6): 177-189, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31713780

RESUMO

In hepatocellular carcinoma (HCC), the hypoxic tumor microenvironment can drive enhance tumor malignancy and recurrence. The microRNA (miRNA) miR-196-5p has been shown to modulate the progression of several cancer types, but its roles in HCC remain uncertain. In the present report we observed significant miR-196-5p downregulation in HCC tissues and cells, and we found that the expression of this miRNA significantly impaired the proliferation and metastatic potential of HCC in vitro and in vivo. We identified high-mobility group AT-hook 2 (HMGA2) as a miR-196-5p target gene that was associated with the ability of miR-196-5p to modulate the progression of HCC. Expression of miR-196-5p and HMGA2 were correlated with the clinical characteristics and poor outcomes in patients with HCC. Finally, we found that hypoxic conditions were linked with reduced miR-196-5p expression in the context of HCC. Together these results highlight the role for miR-196-5p as an inhibitor of the proliferation and metastasis of HCC via the targeting of HMGA2, with this novel hypoxia/miR-196-5p/HMGA2 pathway serving as a potential target for future therapeutic intervention.

3.
Pathol Res Pract ; 215(12): 152674, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31732382

RESUMO

Hepatocellular carcinoma (HCC) is among the most frequently observed forms of cancer. MicroRNAs (miRNAs) are increasingly thought to play a key role in regulating the onset and progression of a wide range of cancer types. In the present report, we found that miR-455-5p expression was significantly decreased in both HCC patient tumor tissues and cell lines, and that this reduction in expression was linked to poorer patient outcomes. When we overexpressed miR-455-5p in HCC cell lines (Huh7 and HepG2), this was linked with impaired proliferation, colony formation, migration, and invasion. We further found that this miRNA was able to directly bind the insulin growth factor receptor (IGF-1R) 3'-untranslated region, thereby suppressing IGF-1R expression in HCC cells. Consistent with this, miR-455-5p overexpression was associated with reduced glucose transporter (GLUT) 1 expression, which in turn inhibited HCC cell uptake of glucose, production of lactate, and generation of ATP. Together these results thus indicate that mIR-455-5p is able to suppress tumor functionality via impairing glycolysis in HCC cells, highlighting this miRNA as a potential target for anti-cancer therapeutic interventions.

4.
Surg Oncol ; 31: 67-74, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31541909

RESUMO

The molecular mechanisms governing the metastasis of colorectal cancer (CRC) are incompletely understood. In the present study, we found NOVA1 to be expressed at higher levels in CRC cell lines and tissue samples, and this upregulation was positively correlated with TNM stage (p = 0.034), poor differentiation (p = 0.001), and lymph node metastasis (p = 0.008). Both overall survival (OS) and relapse-free survival (RFS) were both significantly decreased in patients with high NOVA1 expression relative to those with low expression. Through a multivariate analysis, we determined that NOVA1 independently predicted poor outcomes in those with CRC. In further functional studies, we found that NOVA1 expression controlled the proliferation and invasive characteristics of CRC cells via a mechanism wherein NOVA1 bound and stabilized the IL6 mRNA, enhancing IL-6/JAK2/STAT3 signaling to in turn upregulate matrix metalloproteinases (MMPs) 2, 7, and 9. NOVA1 therefore plays key functional roles in regulating CRC progression, and our results further indicate that it serve as a valuable prognostic biomarker and potentially a target for therapeutic treatment in individuals with CRC.

5.
Sci Rep ; 9(1): 9820, 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285444

RESUMO

MicroRNA-212-3p inhibits several human cancers but its effects on hepatocellular carcinoma (HCC) remain unclear. In this study, we show that miR-212-3p is down-regulated in HCC cell lines and tissues, and correlates with vascular invasion (p = 0.001), and the absence of capsule formation (p = 0.009). We found that miR-212-3p influenced the epithelial to mesenchymal transition (EMT) of HCCLM3 and Huh7 cells. Mechanistically, miR-212-3p repressed cell invasion through the suppression of connective tissue growth factor (CTGF). We therefore validate the anti-HCC effects of miR-212-3p through its ability to suppress CTGF and subsequent EMT.

6.
Oncol Lett ; 17(2): 2317-2327, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30675297

RESUMO

MicroRNAs (miRNAs) serve an important regulatory role in carcinogenesis and cancer progression. Aberrant expression of miR-197-3p has been reported in various human malignancies. However, the role of miR-197-3p in the progression and prognosis of hepatocellular carcinoma (HCC) remains unknown. The present study demonstrated that miR-197-3p was downregulated in HCC tissues and that the low level of miR-197-3p expression in HCC tumours correlated with aggressive clinicopathological characteristics; thus, miR-197-3p may serve as a predictor for poor prognosis in patients with HCC. Additionally, miR-197-3p markedly inhibited the metastasis of HCC cells in vitro and in vivo. Bioinformatics analysis further identified zinc finger protein interacted with K protein 1 (ZIK1) as a novel target of miR-197-3p in HCC cells. These findings suggest that miR-197-3p may regulate the survival of HCC cells, partially through the downregulation of ZIK1. Therefore, the miR-197-3p/ZIK1 axis may serve as a novel therapeutic target in patients with HCC.

7.
Oncotarget ; 8(12): 18872-18884, 2017 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-28122351

RESUMO

Aberrant chromobox (CBX) family protein expression has been reported in a variety of human malignancies. However, the role of CBX6 in hepatocellular carcinoma (HCC) progression and patient prognosis remains unknown. In this study, we found that CBX6 was frequently up-regulated in HCC clinical samples and HCC cell lines and that CBX6 expression was significantly correlated with larger tumor sizes (≥ 5 cm, p = 0.011) and multiple tumors (n ≥ 2, p = 0.018). Survival analyses indicated that patients with higher CBX6 expression levels had significantly shorter recurrence-free survival (RFS) and overall survival (OS) than patients with lower CBX6 expression levels, and multivariate analyses confirmed that increased CBX6 expression was an independent unfavorable prognostic factor for HCC patients. Functional study demonstrated that CBX6 profoundly promoted HCC cell growth both in vitro and in vivo, and mechanistic investigation revealed that the S100A9/NF-κB/MAPK pathway was essential for mediating CBX6 function. In conclusion, our results represent the first evidence that CBX6 contributes to tumor progression and indicate that the protein may serve as a novel prognostic biomarker for HCC and as a therapeutic target in the treatment of the disease.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Proteínas do Grupo Polycomb/biossíntese , Adulto , Idoso , Animais , Western Blotting , Carcinoma Hepatocelular/mortalidade , Progressão da Doença , Intervalo Livre de Doença , Feminino , Xenoenxertos , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Análise Serial de Tecidos
8.
Oncotarget ; 7(38): 62327-62339, 2016 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-27694689

RESUMO

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Despite the therapeutic advances that have been achieved during the past decade, the molecular pathogenesis underlying HCC remains poorly understood. In this study, we discovered that increased expression eukaryotic translation initiation factor 5B (eIF5B) was significantly correlated with aggressive characteristics and associated with shorter recurrence-free survival (RFS) and overall survival (OS) in a large cohort. We also found that eIF5B promoted HCC cell proliferation and migration in vitro and in vivo partly through increasing ASAP1 expression. Our findings strongly suggested that eIF5B could promote HCC progression and be considered a prognostic biomarker for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Fatores de Iniciação em Eucariotos/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células , Intervalo Livre de Doença , Seguimentos , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Fígado/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Prognóstico , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Análise Serial de Tecidos , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Surg Oncol ; 25(3): 171-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27566019

RESUMO

The caudal-type homeobox 1 (CDX1) transcription factor is a member of the caudal-related homeobox transcription factor gene family and has been reported to be down-regulated in a variety of cancers. However, the expression status and significance of CDX1 in hepatocellular carcinoma (HCC) is still controversial, and little is known about the role of CDX1 in HCC·In our previous study, we investigated the expression and clinical significance of CDX1 in HCC samples from 313 HCC patients. We found CDX1 was strikingly down-regulated in HCC samples. CDX1 expression was associated with poor differentiation (P = 0.002), and patients with low CDX1 expression had a significantly poorer prognosis. A subgroup analysis revealed a difference in prognosis between groups with low and high CDX1 expression among patients who had tumors <5 cm in size and who were alpha-fetoprotein (AFP) negative. Moreover, low expression was more frequently observed in the early recurrence group (within 2 years, P = 0.002). In addition, multivariate Cox regression analysis indicated that the CDX1 expression level, tumor size, presence of hepatitis B e antigen (HBeAg), vascular invasion, and presence of hepatitis B surface antigen (HBsAg) were independent risk factors for HCC recurrence, and the CDX1 expression level, tumor size, tumor number, and presence of HBsAg were independent predictor of overall survival of HCC patients. In conclusion, the downregulation of CDX1 is associated with poor prognosis; and it may serve as a novel predictor of the prognosis of HCC patients after curative resection.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/patologia , Hepatectomia/efeitos adversos , Proteínas de Homeodomínio/metabolismo , Neoplasias Hepáticas/patologia , Recidiva Local de Neoplasia/patologia , Complicações Pós-Operatórias , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirurgia , Feminino , Seguimentos , Proteínas de Homeodomínio/genética , Humanos , Técnicas Imunoenzimáticas , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida
10.
Mol Pharm ; 12(2): 644-52, 2015 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-25495890

RESUMO

Targeted delivery system would be an interesting platform to enhance the therapeutic effect and to reduce the side effects of anticancer drugs. In this study, we have developed lactobionic acid (LA)-modified chitosan-stearic acid (CS-SA) (CSS-LA) to deliver doxorubicin (DOX) to hepatic cancer cells. The average particle size of CSS-LA/DOX was ∼100 nm with a high entrapment efficiency of >95%. Drug release studies showed that DOX release from pH-sensitive micelles is significantly faster at pH 5.0 than at pH 7.4. The LA conjugated micelles showed enhanced cellular uptake in HepG2 and BEL-7402 liver cancer cells than free drug and unconjugated micelles. Consistently, CSS-LA/DOX showed enhanced cell cytotoxicity in these two cell lines. Annexin-V/FITC and PI based apoptosis assay showed that the number of living cells greatly reduced in this group with marked presence of necrotic and apoptotic cells. LA-conjugated carrier induced typical chromatic condensation of cells; membrane blebbing and apoptotic bodies began to appear. In vivo, CSS-LA/DOX showed an excellent tumor regression profile with no toxic side effects. The active targeting moiety, long circulation profile, and EPR effect contributed to its superior anticancer effect in HepG2 based tumor. Our results showed that polymeric micelles conjugated with LA increased the therapeutic availability of DOX in the liver cancer cell based solid tumor without any toxic side effects. The active targeting ligand conjugated nanoparticulate system could be a promising therapeutic strategy in the treatment of hepatic cancers.


Assuntos
Quitosana/química , Doxorrubicina/administração & dosagem , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Neoplasias Hepáticas/tratamento farmacológico , Micelas , Polímeros/química , Ácidos Esteáricos/química , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Dissacarídeos/química , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Células Hep G2 , Humanos , Camundongos Nus , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Gastrointest Surg ; 17(8): 1414-21, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23715650

RESUMO

BACKGROUND: The duration of hepatic vascular inflow occlusion and the amount of intraoperative blood loss have significant negative impacts on postoperative morbidity, mortality and long-term survival outcomes of patients who receive partial hepatectomy for hepatocellular carcinoma (HCC) with cirrhosis. AIM: This study aimed to compare the perioperative outcomes of partial hepatectomy for HCC superimposed on hepatitis B-related cirrhosis using two different occlusion techniques. METHODS: A randomized controlled trial was carried out to evaluate the impact of two different vascular inflow occlusion techniques. The postoperative short-term results were compared. RESULTS: During the study period, 252 patients received partial hepatectomy for HCC with cirrhosis. Of these patients, 120 were randomized equally into two groups: the Pringle manoeuvre group (n = 60) and the hemi-hepatic vascular inflow occlusion group (n = 60). The number of patients who had poor liver function on postoperative day 5 with ISLGS grade B or worse was 24 and 13, respectively (P = 0.030). The postoperative complication rate was significantly higher in the Pringle manoeuvre group (40 versus 22 %, P = 0.030). However, the Pringle manoeuvre group had significantly shorter operating time (116 versus 136 min, P = 0.012) although there was no significant difference in intraoperative blood loss between the two groups [200 ml (range 10-5,000 ml) versus 300 ml (range 100-1,000 ml); P = 0.511]. There was no perioperative mortality. CONCLUSIONS: The results indicated that for patients with HCC with cirrhosis, hemi-hepatic vascular inflow occlusion was a better inflow occlusion method than Pringle manoeuvre.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Carcinoma Hepatocelular/cirurgia , Hepatectomia/métodos , Neoplasias Hepáticas/cirurgia , Fígado/irrigação sanguínea , Idoso , Volume Sanguíneo , Carcinoma Hepatocelular/complicações , Feminino , Hepatectomia/efeitos adversos , Humanos , Fígado/fisiopatologia , Cirrose Hepática/complicações , Testes de Função Hepática , Neoplasias Hepáticas/complicações , Masculino , Pessoa de Meia-Idade , Duração da Cirurgia
12.
Zhonghua Wei Chang Wai Ke Za Zhi ; 12(4): 404-8, 2009 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-19598030

RESUMO

OBJECTIVE: To investigate the effect of CD8(+)CD28(-) suppressor T cells(Ts) induced by dendritic cell(DC) with major histocompatibility complex 1(MHC-1) expression RNA interference on immune tolerance in rat intestinal transplantation. METHODS: The expression level of CD8(+)CD28(-)Ts were successfully induced by DC with MHC-1 expression interfered by RNA interference technique under the stimulator of allograft antigen. Orthotopic intestinal transplantation was performed in 36 rats by modified three cuffs method. The recipients were randomly divided into three groups(12 rats in each group):group A was experimental group with CD8(+)CD28(-) Ts being administrated, mixed T cells were injected in group B, while in group C, NS were administrated. On the first day and the seventh day posttransplant, the 36 rats of the 3 groups were administrated through vena dorsalis penis respectively. Six rats were selected randomly from each group and the animals were sacrificed on the 14 th day postoperatively, serum levels of TGF-beta, IFN-gamma and the values of Na(+)-K(+)-ATPase activity of the intestinal graft were assayed and the intestinal pathologic morphology, intestinal allograft survival were observed concerning the remainders. RESULTS: On the 14 th day after operation, the expression levels of TGF-beta and IFN-gamma in group A were significantly up-regulated as compared with those in group B and group C(P<0.05). Na(+)-K(+)-ATPase activity in group A was(6.3+/-1.0) kU/g, much higher than the levels of group B(3.6+/-0.9)kU/g and group C(2.9+/-1.3) kU/g and the differences were significant(P<0.05). The data suggested preliminarily that pathological scores of intestinal graft in group A were lower than those in group B and group C. The survival time of the recipients in group A was 32.0 days, much longer than that in group B (17.5 days, P<0.05) and group C(21.0 days, P<0.05). CONCLUSION: CD8(+)CD28(-) Ts induced by DC with MHC-1 expression RNA interference can alleviate acute rejection and lead to immune tolerance in rat intestinal transplantation.


Assuntos
Células Dendríticas/imunologia , Intestino Delgado/imunologia , Interferência de RNA , Linfócitos T Reguladores/imunologia , Tolerância ao Transplante/imunologia , Animais , Células Dendríticas/metabolismo , Tolerância Imunológica , Intestino Delgado/transplante , Complexo Principal de Histocompatibilidade/imunologia , Masculino , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Transplante Homólogo/imunologia
13.
Zhonghua Wei Chang Wai Ke Za Zhi ; 12(1): 65-8, 2009 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-19145508

RESUMO

OBJECTIVE: To investigate operative techniques, treatment and precaution of common complications of orthotopic intestinal transplantation in the rats. METHODS: Orthotopic intestinal transplantation was performed in 120 rats by modified three cuffs method. The causes, treatment and precaution of common complications were analyzed retrospectively. RESULTS: The 7-day survival rate of recipients was 82.5% and the 30-day survival rate was 68.3%. The average volume of bleeding in the recipient operation was less than 1 ml. The result obtained from the above 99 recipients was satisfactory. The main reasons of final failure and death were as follows: anastomotic bleeding(5 rats), portal vein thrombus(2 rats), arterial thrombus(4 rats), air embolism(1 rat), infection of abdominal cavity(4 rats), aspiration pneumonitis (2 rats), anesthetic accident(2 rats) and kinking of graft intestine(1 rat). CONCLUSIONS: The sophisticated surgical technique and the delicate surgical manipulation are the prerequisite of preventing operational complication. Improving operative techniques and being familiar with the common complications can reduce the occurrence of complications and increase operative successful rate.


Assuntos
Intestinos/transplante , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Complicações Pós-Operatórias , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Transplante Homólogo
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