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1.
Biochem Biophys Res Commun ; 586: 93-99, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34837838

RESUMO

Dysregulated activation of the WNT/ß-catenin signaling pathway is essential for the initiation and development of various cancers. E7386, a small-molecule compound, attenuates WNT signaling by blocking the interaction between ß-catenin and CREB-binding protein (CBP); hence, it is regarded as a therapeutic candidate for cancers with activated WNT signaling. In the present study, we evaluated the biological characteristics associated with E7386 sensitivity by using a panel of patient-derived colon cancer spheroids. An integrative approach that combined E7386 sensitivity and gene expression profiles revealed that the resistance of the cancer spheroids to E7386 was associated with the activation of the NF-κB pathway. NF-κB pathway inhibitors acted synergistically with E7386 to block proliferation and induce cell cycle arrest in E7386-resistant spheroids. These findings suggest a possibility that a combination of E7386 and NF-κB inhibition may effectively block the proliferation of a subset of colon cancer cells.

2.
Cancer Lett ; 521: 29-38, 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34419499

RESUMO

Patient-derived cells and xenografts retain the biological characteristics of clinical cancers and are instrumental in gaining a better understanding of the chemoresistance of cancer cells. Here, we have established a panel of patient-derived spheroids from clinical materials of ovarian cancer. Systematic evaluation using therapeutic agents indicated that sensitivity to platinum-based compounds significantly varied among the spheroids. To understand the molecular basis of drug sensitivity, we performed integrative analyses combining chemoresistance data and gene expression profiling of the ovarian cancer patient-derived spheroids. Correlation analyses revealed that cisplatin resistance was significantly associated with elevated levels of glucose-6-phosphate dehydrogenase (G6PD) and glutathione-producing redox enzymes. Accordingly, cisplatin-resistant spheroids established in vitro showed elevated levels of G6PD and active glutathione. Moreover, treatment with a G6PD inhibitor in combination with cisplatin suppressed spheroid proliferation in vitro and largely eradicated peritoneal metastasis in mouse xenograft models. Furthermore, G6PD expression was elevated during carcinogenesis and associated with poor prognosis. Thus, the combination of gene expression data and chemosensitivity revealed the essential roles of G6PD-driven redox metabolism in cisplatin resistance, underscoring the significance of an integrative approach using patient-derived cells.

3.
Cancer Res ; 80(20): 4451-4464, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-32816913

RESUMO

Cancer chemoresistance is often attributed to the presence of cancer stem cell (CSC)-like cells, but whether they are homogeneously chemoresistant remains unclear. We previously showed that in colon tumors, a subpopulation of LGR5+ CSC-like cells driven by TCF1 (TCF7), a Wnt-responsive transcription factor, were responsible for tumorigenicity. Here we demonstrate that the tumorigenic subpopulation of mouse LGR5+ cells exists in a slow-cycling state and identify a unique 22-gene signature that characterizes these slow-cycling CSC. Seven of the signature genes are specifically expressed in slow-cycling LGR5+ cells from xenografted human colon tumors and are upregulated in colon cancer clinical specimens. Among these seven, four genes (APCDD1, NOTUM, PROX1, and SP5) are known to be direct Wnt target genes, and PROX1 was expressed in the invasive fronts of colon tumors. PROX1 was activated by TCF1 to induce CDKN1C and maintain a slow-cycling state in colon cancer organoids. Strikingly, PROX1 was required for recurrent growth after chemotherapeutic treatment, suggesting that inhibition of slow-cycling CSC by targeting the TCF1-PROX1-CDKN1C pathway is an effective strategy to combat refractory colon cancer in combination with conventional chemotherapy. SIGNIFICANCE: These findings illustrate the importance of a slow-cycling CSC subpopulation in colon cancer development and chemoresistance, with potential implications for the identified slow-cycling CSC signatures and the TCF1-PROX1-CDKN1C pathway as therapeutic targets.


Assuntos
Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Homeodomínio/efeitos adversos , Células-Tronco Neoplásicas/patologia , Proteínas Supressoras de Tumor/efeitos adversos , Animais , Inibidor de Quinase Dependente de Ciclina p57/genética , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Camundongos Endogâmicos C57BL , Receptores Acoplados a Proteínas G/genética , Análise de Sequência de RNA , Análise de Célula Única , Esferoides Celulares/patologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
Int J Cancer ; 147(11): 3224-3235, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32818320

RESUMO

The cystine/glutamate antiporter, system xc - , is essential for the efficient uptake of cystine into cells. Interest in the mechanisms of system xc - function soared with the recognition that system xc - presents the most upstream node of ferroptosis, a recently described form of regulated necrosis relevant for degenerative diseases and cancer. Since targeting system xc - hold the great potential to efficiently combat tumor growth and metastasis of certain tumors, we disrupted the substrate-specific subunit of system xc - , xCT (SLC7A11) in the highly metastatic mouse B16F10 melanoma cell line and assessed the impact on tumor growth and metastasis. Subcutaneous injection of tumor cells into the syngeneic B16F10 mouse melanoma model uncovered a marked decrease in the tumor-forming ability and growth of KO cells compared to control cell lines. Strikingly, the metastatic potential of KO cells was markedly reduced as shown in several in vivo models of experimental and spontaneous metastasis. Accordingly, survival rates of KO tumor-bearing mice were significantly prolonged in contrast to those transplanted with control cells. Analyzing the in vitro ability of KO and control B16F10 cells in terms of endothelial cell adhesion and spheroid formation revealed that xCT expression indeed plays an important role during metastasis. Hence, system xc - emerges to be essential for tumor metastasis in mice, thus qualifying as a highly attractive anticancer drug target, particularly in light of its dispensable role for normal life in mice.


Assuntos
Sistema y+ de Transporte de Aminoácidos/genética , Técnicas de Inativação de Genes/métodos , Melanoma/patologia , Animais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/genética , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Taxa de Sobrevida
5.
Inflamm Res ; 67(10): 839-846, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30056535

RESUMO

OBJECTIVE: In sporadic colon tumors, multistep process of well-known genetic alterations accelerates carcinogenesis; however, this does not appear to be the case in inflammation-related ones. We previously established a model of inflammation-related colon carcinogenesis using human colonic adenoma cells, and identified fascin as a driver gene of this process. We analyzed the microRNAs involved in the stable fascin expression in colon adenocarcinoma cells. MATERIALS AND METHODS: miRNA microarray analysis was performed using FPCK-1-1 adenoma cells and its-derived FPCKpP1-4 adenocarcinoma cells through chronic inflammation. To assess the involvement of miRNA in the inflammation-related carcinogenesis, sphere-forming ability, expression of colon cancer stemness markers, and stability of fascin protein via the proteasome using tough decoy RNA technique. RESULTS: We found that 17 miRNAs including miR-146a were upregulated and 16 miRNAs were downregulated in FPCKpP1-4 adenocarcinoma cells. We revealed that miR-146a in the adenocarcinoma cells brought about acquisition of sphere formation, cancer stemness, and inhibition of proteasomal degradation of the fascin protein. CONCLUSIONS: We found that stable fascin expression is brought about via the inhibition of proteasome degradation by miR-146a in the process of a chronic inflammation-related colon carcinogenesis.


Assuntos
Adenocarcinoma/metabolismo , Proteínas de Transporte/metabolismo , Neoplasias do Colo/metabolismo , Inflamação/metabolismo , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Linhagem Celular Tumoral , Doença Crônica , Humanos
6.
Sci Rep ; 8(1): 2251, 2018 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-29396565

RESUMO

The delivery of hydrophilic macromolecules runs into difficulties such as penetration of the cell membrane lipid bilayer. Our prior experiment demonstrated that capsaicin induces the reversible opening of tight junctions (TJs) and enhances the delivery of hydrophilic macromolecules through a paracellular route. Herein, we screened paracellular permeability enhancers other than capsaicin. As TJ opening by capsaicin is associated with Ca2+ influx, we first screened the compounds that induce Ca2+ influx in layered MDCK II cells, and then we determined the compounds' abilities to open TJs. Our results identified several natural compounds with α,ß-unsaturated moiety. A structure-activity relationship (SAR) analysis and the results of pretreatment with reducing reagent DTT suggested the importance of α,ß-unsaturated moiety. We also examined the underlying mechanisms, and our findings suggest that the actin reorganization seen in capsaicin treatment is important for the reversibility of TJ opening. Furthermore, our analyses revealed that TRPA1 is involved in the Ca2+ influx and TJ permeability increase not only by an α,ß-unsaturated compound but also by capsaicin. Our results indicate that the α,ß-unsaturated moiety can be a potent pharmacophore for TJ opening.


Assuntos
Capsaicina/metabolismo , Permeabilidade/efeitos dos fármacos , Canal de Cátion TRPA1/metabolismo , Junções Íntimas/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Cálcio/metabolismo , Cães , Células Madin Darby de Rim Canino
7.
Int J Mol Sci ; 18(4)2017 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-28422073

RESUMO

A sustained and chronically-inflamed environment is characterized by the presence of heterogeneous inflammatory cellular components, including neutrophils, macrophages, lymphocytes and fibroblasts. These infiltrated cells produce growth stimulating mediators (inflammatory cytokines and growth factors), chemotactic factors (chemokines) and genotoxic substances (reactive oxygen species and nitrogen oxide) and induce DNA damage and methylation. Therefore, chronic inflammation serves as an intrinsic niche for carcinogenesis and tumor progression. In this article, we summarize the up-to-date findings regarding definitive/possible causes and mechanisms of inflammation-related carcinogenesis derived from experimental and clinical studies. We also propose 10 strategies, as well as candidate agents for the prevention of inflammation-related carcinogenesis.


Assuntos
Carcinogênese/efeitos dos fármacos , Quimioprevenção , Inflamação/complicações , Neoplasias/etiologia , Neoplasias/prevenção & controle , Animais , Quimioprevenção/métodos , Doença Crônica , Citocinas/metabolismo , Dano ao DNA , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Espécies Reativas de Nitrogênio , Espécies Reativas de Oxigênio
8.
Sci Rep ; 7: 43567, 2017 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-28272394

RESUMO

Since liver metastasis is the main cause of death in cancer patients, we attempted to identify the driver gene involved. QRsP-11 fibrosarcoma cells were injected into the spleens of syngeneic mice to isolate tumour sub-populations that colonize the liver. Cells from liver metastatic nodules were established and subsequently injected intrasplenically for selection. After 12 cycles, the cell subline LV12 was obtained. Intravenous injection of LV12 cells produced more liver metastases than QRsP-11 cells, whereas the incidence of lung metastases was similar to that of QRsP-11 cells. LV12 cells adhered to liver-derived but not to lung-derived endothelial cells. DNA chip analysis showed that amphoterin-induced gene and open reading frame 2 (Amigo2) was overexpressed in LV12 cells. siRNA-mediated knockdown of Amigo2 expression in LV12 cells attenuated liver endothelial cell adhesion. Ex vivo imaging showed that suppression of Amigo2 in luciferase-expressing LV12 cells reduced attachment/metastasis to liver to the same level as that observed with QRsP-11 cells. Forced expression of Amigo2 in QRsP-11 cells increased liver endothelial cell adhesion and liver metastasis. Additionally, Amigo2 expression in human cancers was higher in liver metastatic lesions than in primary lesions. Thus, Amigo2 regulated tumour cell adhesion to liver endothelial cells and formation of liver metastases.


Assuntos
Adesão Celular/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/secundário , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Animais , Biomarcadores Tumorais , Linhagem Celular Tumoral , Neoplasias do Colo/genética , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Neoplasias Hepáticas/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia
9.
J Antibiot (Tokyo) ; 70(5): 691-694, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28096546

RESUMO

MA026 is an antiviral natural compound against hepatitis C virus (HCV). It was recently reported that MA026 binds claudin-1 (CLDN1) and inhibits HCV infection. Although CLDN1 is an important component of tight junctions (TJ) in the epithelial cell layer, the effects of MA026 on the TJ barrier function remained to be revealed. Here we report that MA026 irreversibly opens the TJ. MA026 irreversibly increased FD4 permeability and decreased transepithelial electrical resistance (TER) for at least 5 h. Although MA026 increased Ca2+ influx in layered MDCKII cells, the Ca2+ influx was less than that of capsaicin, a reversible TJ opener. Moreover, MA026 did not induce the dephosphorylation of cofilin and reorganization of F-actin structure. Although the mechanism is left to be disclosed, these results suggest that MA026 is a novel irreversible TJ opener probably by targeting CLDN1.


Assuntos
Antivirais/farmacologia , Claudina-1/metabolismo , Depsipeptídeos/farmacologia , Células Epiteliais/efeitos dos fármacos , Junções Íntimas/efeitos dos fármacos , Animais , Cálcio/metabolismo , Capsaicina/farmacologia , Membrana Celular/metabolismo , Cães , Impedância Elétrica , Células Epiteliais/metabolismo , Células Madin Darby de Rim Canino , Junções Íntimas/metabolismo , Fatores de Tempo
10.
Cancer Med ; 5(5): 892-902, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26817521

RESUMO

Despite recent improvements in the therapy for osteosarcoma, 30-40% of osteosarcoma patients die of this disease, mainly due to its lung metastasis. We have previously reported that intravenous injection of miR-143 significantly suppresses lung metastasis of human osteosarcoma cells (143B) in a mouse model. In this study, we examined the biological role and mechanism of miR-143 in the metastasis of human osteosarcoma cells. We identified plasminogen activator inhibitor-1 (PAI-1) as a direct target gene of miR-143. To determine the role of PAI-1 in human osteosarcoma cells, siRNA was transfected into 143B cells for knockdown of PAI-1 expression. An in vitro study showed that downregulation of PAI-1 suppressed cell invasion activity, but not proliferation. Moreover, injection of PAI-1 siRNA into a primary lesion in the osteosarcoma mouse model inhibited lung metastasis compared to control siRNA-injected mice, without influencing the proliferative activity of the tumor cells. Subsequent examination using 143B cells revealed that knockdown of PAI-1 expression resulted in downregulation of the expression and secretion of matrix metalloproteinase-13 (MMP-13), which is also a target gene of miR-143 and a proteolytic enzyme that regulates tumor-induced osteolysis. Immunohistochemical analysis using clinical samples showed that higher miR-143 expressing cases showed poor expression of PAI-1 in the primary tumor cells. All such cases belonged to the lung metastasis-negative group. Moreover, the frequency of lung metastasis-positive cases was significantly higher in PAI-1 and MMP-13 double-positive cases than in PAI-1 or MMP-13 single-positive or double-negative cases (P < 0.05). These results indicated that PAI-1, a target gene of miR-143, regulates invasion and lung metastasis via enhancement of MMP-13 expression and secretion in human osteosarcoma cells, suggesting that these molecules could be potential therapeutic target genes for preventing lung metastasis in osteosarcoma patients.


Assuntos
Neoplasias Ósseas/genética , Metaloproteinase 13 da Matriz/biossíntese , MicroRNAs/genética , Osteossarcoma/genética , Inibidor 1 de Ativador de Plasminogênio/genética , Animais , Neoplasias Ósseas/patologia , Proliferação de Células/genética , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes/métodos , Xenoenxertos , Humanos , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/secundário , Masculino , Camundongos Nus , MicroRNAs/fisiologia , Invasividade Neoplásica/genética , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Osteossarcoma/patologia , Osteossarcoma/secundário , RNA Interferente Pequeno/genética , Transfecção , Células Tumorais Cultivadas , Regulação para Cima/genética
11.
Nutrients ; 7(12): 10237-50, 2015 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-26670250

RESUMO

We have established an inflammation-related carcinogenesis model in mouse, in which regressive QR-32 cells subcutaneously co-implanted with a foreign body-gelatin sponge-convert themselves into lethal tumors due to massive infiltration of inflammatory cells into the sponge. Animals were fed with a diet containing 5% or 10% fermented brown rice and rice bran with Aspergillus oryzae (FBRA). In 5% and 10% FBRA diet groups, tumor incidences were lower (35% and 20%, respectively) than in the non-treated group (70%). We found that FBRA reduced the number of inflammatory cells infiltrating into the sponge. FBRA administration did not cause myelosuppression, which indicated that the anti-inflammatory effects of FBRA took place at the inflammatory lesion. FBRA did not have antitumor effects on the implanted QRsP-11 tumor cells, which is a tumorigenic cell line established from a tumor arisen after co-implantation of QR-32 cells with sponge. FBRA did not reduce formation of 8-hydroxy-2'-deoxyguanine adducts, a marker of oxidative DNA damage in the inflammatory lesion; however, it reduced expression of inflammation-related genes such as TNF-α, Mac-1, CCL3 and CXCL2. These results suggest that FBRA will be an effective chemopreventive agent against inflammation-related carcinogenesis that acts by inhibiting inflammatory cell infiltration into inflammatory lesions.


Assuntos
Aspergillus oryzae/metabolismo , Dieta , Fermentação , Inflamação/prevenção & controle , Neoplasias/prevenção & controle , Oryza/microbiologia , Animais , Carcinogênese , Quimiocina CCL3/genética , Quimiocina CCL3/metabolismo , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Dano ao DNA , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Oryza/química , Estresse Oxidativo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
12.
J Exp Neurosci ; 9: 27-35, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25987850

RESUMO

In the present study, the effects of morphine were examined on tests of spatial memory, object exploration, locomotion, and anxiety in male ICR mice. Administration of morphine (15 or 30 mg/kg, intraperitoneally (i.p.)) induced a significant decrease in Y-maze alternations compared to saline vehicle-treated mice. The reduced Y-maze alternations induced by morphine were completely blocked by naloxone (15 mg/kg) or ß-funaltrexamine (5 mg/kg) but not by norbinaltorphimine (5 mg/kg) or naltrindole (5 mg/kg), suggesting that the morphine-induced spatial memory impairment was mediated predominantly by µ-opioid receptors (MOPs). Significant spatial memory retrieval impairments were observed in the Morris water maze (MWM) in mice treated with morphine (15 mg/kg) or scopolamine (1 mg/kg), but not with naloxone or morphine plus naloxone. Reduced exploratory time was observed in mice after administration of morphine (15 mg/kg), in a novel-object exploration test, without any changes in locomotor activity. No anxiolytic-like behavior was observed in morphine-treated mice in the elevated plus maze. A significant reduction in buried marbles was observed in morphine-treated mice measured in the marble-burying test, which was blocked by naloxone. These observations suggest that morphine induces impairments in spatial short-term memory and retrieval, and reduces exploratory behavior, but that these effects are not because of overall changes in locomotion or anxiety.

13.
Proteomics ; 14(9): 1031-41, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24574163

RESUMO

By a proteomics-based approach, we identified an overexpression of fascin in colon adenocarcinoma cells (FPCKpP-3) that developed from nontumorigenic human colonic adenoma cells (FPCK-1-1) and were converted to tumorigenic by foreign-body-induced chronic inflammation in nude mice. Fascin overexpression was also observed in the tumors arising from rat intestinal epithelial cells (IEC 6) converted to tumorigenic in chronic inflammation which was induced in the same manner. Upregulation of fascin expression in FPCK-1-1 cells by transfection with sense fascin cDNA converted the cells tumorigenic, whereas antisense fascin-cDNA-transfected FPCKpP-3 cells reduced fascin expression and lost their tumor-forming ability in vivo. The tumorigenic potential by fascin expression was consistent with their ability to survive and grow in the three-dimensional multicellular spheroids. We found that resistance to anoikis (apoptotic cell death as a consequence of insufficient cell-to-substrate interactions), which is represented by the three-dimensional growth of solid tumors in vivo, was regulated by fascin expression through caspase-dependent apoptotic signals. From these, we demonstrate that fascin is a potent suppressor to caspase-associated anoikis and accelerator of the conversion of colonic adenoma cells into adenocarcinoma cells by chronic inflammation.


Assuntos
Anoikis/fisiologia , Proteínas de Transporte/metabolismo , Neoplasias do Colo/metabolismo , Inflamação/metabolismo , Proteínas dos Microfilamentos/metabolismo , Animais , Proteínas de Transporte/análise , Proteínas de Transporte/genética , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Nus , Proteínas dos Microfilamentos/análise , Proteínas dos Microfilamentos/genética , Ratos , Esferoides Celulares/metabolismo , Células Tumorais Cultivadas/metabolismo
14.
Int J Oncol ; 44(1): 53-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24212760

RESUMO

Early detection and treatment are critical in the management of renal cell carcinoma (RCC). However, there is no standard serum biomarker to facilitate early diagnosis or prognostic stratification in patients with RCC. Recent reports suggest that circulating microRNAs (miRNAs) have great potential as biomarkers for diagnosis and prognosis in patients with several types of cancers. Further, many studies using miRNA microarray analysis demonstrated that miR-210 expression in clear cell carcinoma (CCC), which is the largest subtype of RCC, was significantly upregulated in tumor tissue. Therefore, we investigated whether serum miR-210 could be a useful biomarker for the diagnosis and progression of CCC. This study included 34 CCC patients and 23 healthy controls (HC). First, we analyzed tissue miR-210 levels in tumor tissues and matched normal tissues from the 34 CCC patients. Second, we investigated the serum miR-210 levels in the 34 CCC patients and the 23 HC patients. Real-time polymerase chain reaction (PCR) was used to measure miRNA levels. Moreover, we examined the correlation between serum miR-210 levels and the clinicopathological parameters. Among patients with CCC, expression of miR-210 was higher in tumor tissues compared to normal tissues (P<0.001). Serum miR-210 levels were higher in CCC patients compared to HCs (P=0.001). Receiver operating characteristic (ROC) curve analysis showed an area under the ROC curve (AUC) of 0.77 (95% confidence interval, 0.65-0.89) and a sensitivity and specificity of 65 and 83%, respectively. In addition, there was no significant association between serum miR-210 levels and age, sex, tumor size or existence of metastasis at diagnosis among the 34 CCC patients. In conclusion, serum miR-210 upregulation may occur in the early stage of CCC and serum miR-210 can be a useful biomarker for early CCC in humans.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Regulação Neoplásica da Expressão Gênica/genética , MicroRNAs/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/patologia , Humanos , Masculino , Pessoa de Meia-Idade
15.
Exp Cell Res ; 319(18): 2835-44, 2013 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-23948305

RESUMO

It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment.


Assuntos
Adenocarcinoma/patologia , Adenoma/patologia , Neoplasias do Colo , Inflamação , Óxido Nítrico/metabolismo , Adenocarcinoma/fisiopatologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Feminino , Guanidinas/farmacologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus
16.
J Am Chem Soc ; 124(44): 12960-1, 2002 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-12405818

RESUMO

A new and highly efficient catalytic system based on CpRuClL2 is proposed for the S-propargylation of thiols by propargylic carbonates under neutral conditions, in which specific requirements inherent to the different reactivities of aliphatic and aromatic thiols are achieved by tuning both the nature of the ancillary ligand L and the experimental conditions.


Assuntos
Alcinos/síntese química , Rutênio/química , Compostos de Sulfidrila/química , Sulfetos/síntese química , Carbamatos/química , Catálise , Compostos Organometálicos/química
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