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1.
Nat Commun ; 10(1): 2510, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175290

RESUMO

Metastasis-associated recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC), however, the underlying mechanisms remain largely elusive. In this study, we report that expression of choroideremia-like (CHML) is increased in HCC, associated with poor survival, early recurrence and more satellite nodules in HCC patients. CHML promotes migration, invasion and metastasis of HCC cells, in a Rab14-dependent manner. Mechanism study reveals that CHML facilitates constant recycling of Rab14 by escorting Rab14 to the membrane. Furthermore, we identify several metastasis regulators as cargoes carried by Rab14-positive vesicles, including Mucin13 and CD44, which may contribute to metastasis-promoting effects of CHML. Altogether, our data establish CHML as a potential promoter of HCC metastasis, and the CHML-Rab14 axis may be a promising therapeutic target for HCC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Neoplasias Primárias Múltiplas/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/secundário , Células HEK293 , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Camundongos , Camundongos Nus , Mucinas/metabolismo , Invasividade Neoplásica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Transplante de Neoplasias , Neoplasias Primárias Múltiplas/patologia , RNA Mensageiro/metabolismo , Carga Tumoral
2.
Cell Prolif ; 52(3): e12583, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30793395

RESUMO

OBJECTIVES: Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. MATERIALS AND METHODS: The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. RESULTS: The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of ß-catenin to the nucleus by activating glycogen synthase kinase-3ß (GSK3ß). Moreover, constitutively active ß-catenin blocked the suppressive effects of WISP3 on HCC. CONCLUSIONS: Our study showed that WISP3 suppressed the progression of HCC by negative regulation of ß-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.


Assuntos
Proteínas de Sinalização Intercelular CCN/genética , Proteínas de Sinalização Intercelular CCN/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Proteínas de Sinalização Intercelular CCN/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Regulação para Baixo , Técnicas de Silenciamento de Genes , Glicogênio Sintase Quinase 3 beta/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Nus , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais , Fatores de Transcrição TCF/metabolismo , beta Catenina/metabolismo
3.
Br J Cancer ; 118(10): 1337-1348, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29717200

RESUMO

BACKGROUND: Chemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown. METHODS: Chemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin. RESULTS: Chemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN-CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo. CONCLUSIONS: Our study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Quimiocinas/administração & dosagem , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , PTEN Fosfo-Hidrolase/genética , Receptores de Quimiocinas/genética , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Movimento Celular , Proliferação de Células , Quimiocinas/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Camundongos , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Metástase Neoplásica , Proteína Oncogênica v-akt/genética , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
4.
J Exp Med ; 215(1): 177-195, 2018 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-29237705

RESUMO

Although cilia loss and cell transformation are frequently observed in the early stage of tumorigenesis, the roles of cilia in cell transformation are unknown. In this study, disrupted ciliogenesis was observed in cancer cells and pancreatic cancer tissues, which facilitated oncogene-induced transformation of normal pancreatic cells (HPDE6C7) and NIH3T3 cells through activating the mevalonate (MVA) pathway. Disruption of ciliogenesis up-regulated MVA enzymes through ß catenin-T cell factor (TCF) signaling, which synchronized with sterol regulatory element binding transcription factor 2 (SREBP2), and the regulation of MVA by ß-catenin-TCF signaling was recapitulated in a mouse model of pancreatic ductal adenocarcinoma (PDAC) and human PDAC samples. Moreover, disruption of ciliogenesis by depleting Tg737 dramatically promoted tumorigenesis in the PDAC mouse model, driven by KrasG12D , which was inhibited by statin, an inhibitor of the MVA pathway. Collectively, this study emphasizes the crucial roles of cilia in governing the early steps of the transformation by activating the MVA pathway, suggesting that statin has therapeutic potential for pancreatic cancer treatment.


Assuntos
Transformação Celular Neoplásica/metabolismo , Cílios/patologia , Redes e Vias Metabólicas , Ácido Mevalônico/metabolismo , Animais , Carcinoma Ductal Pancreático/etiologia , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Humanos , Masculino , Camundongos , Células NIH 3T3 , Oncogenes , Neoplasias Pancreáticas/etiologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteína de Ligação a Elemento Regulador de Esterol 2 , Fatores de Transcrição TCF/metabolismo
5.
J Hepatol ; 65(1): 137-145, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27013087

RESUMO

BACKGROUND & AIMS: Iron is an essential metal for fundamental metabolic processes, but little is known regarding the involvement of iron in other nutritional disorders. In the present study, we investigated disordered iron metabolism in a murine model of hereditary tyrosinemia type I (HT1), a disease of the tyrosine degradation pathway. METHODS: We analysed the status of iron accumulation following NTBC withdrawal from Fah(-/-) mice, a murine model for HT1. Liver histology and serum parameters were used to assess the extent of liver injury and iron deposition. To determine the physiological significance of iron accumulation, mice were subjected to a low-iron food intake to reduce the iron accumulation. Mechanistic studies were performed on tissues and cells using immunoblotting, qRT-PCR, adenovirus transfection and other assays. RESULTS: Severe iron overload was observed in the murine model of HT1 with dramatically elevated hepatic and serum iron levels. Mechanistic studies revealed that downregulation and dysfunction of Tfr2 decreased hepcidin, leading to iron overload. The Fah(-/-) hepatocytes lost the ability of transferrin-sensitive induction of hepcidin. Forced expression of Tfr2 in the murine liver reduced the iron accumulation. Moreover, transcription factor Sp1 was downregulated and identified as a new regulator of Tfr2 here. Additionally, low-iron food intake effectively reduced the iron deposits, protected the liver and prolonged the survival in these mice. CONCLUSIONS: Iron was severely overloaded in the HT1 mice via the Sp1/Tfr2/Hepcidin axis. The iron overload induced liver injury in the HT1 mice, and reduction of the iron accumulation ameliorated liver injury. LAY SUMMARY: Primary and secondary iron overload is an abnormal status affecting millions of people worldwide. Here, we reported severe iron overload in a murine model of HT1, a disease of the tyrosine degradation pathway, and elucidated the mechanistic basis and the physiological significance of iron overload in HT1. These studies are of general interest not only with respect to secondary iron-induced liver injury in HT1 but also are important to elucidate the crosstalk between the two metabolic pathways.


Assuntos
Fígado/lesões , Tirosinemias , Animais , Hepcidinas , Ferro , Sobrecarga de Ferro , Camundongos
6.
Hepatology ; 62(6): 1791-803, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26257239

RESUMO

UNLABELLED: Sorafenib is a specific adenosine triphosphate-competitive RAF inhibitor used as a first-line treatment of advanced hepatocellular carcinoma (HCC). However, the responses are variable, reflecting heterogeneity of the disease, while the resistance mechanism remains poorly understood. Here, we report that sorafenib treatment can exacerbate disease progression in both patient-derived xenografts and cell line-derived xenografts and that the therapeutic effect of the drug inversely covaries to the ratio of epithelial cell adhesion molecule-positive cells, which may be tumor initiating cells in HCC. The TSC2-AKT cascade mediates this sorafenib resistance. In response to sorafenib treatment, formation of the TSC1/2 complex is enhanced, causing increased phosphorylation of AKT, which contributes to up-regulation of "stemness"-related genes in epithelial cell adhesion molecule-positive cells and enhancement of tumorigenicity. The expression of TSC2 negatively correlated with prognosis in clinical sorafenib therapy. Furthermore, all-trans retinoic acid decreased AKT activity, reduced the epithelial cell adhesion molecule-positive cell population enriched by sorafenib, and potentiated the therapeutic effect of sorafenib in the patient-derived xenograft model. CONCLUSION: Our findings suggest that a subtype of HCC is not suitable for sorafenib therapy; this resistance to sorafenib can be predicted by the status of TSC2, and agents inducing differentiation of tumor initiating cells (e.g., all-trans retinoic acid) should improve the prognosis of this subtype of HCC.


Assuntos
Antígenos de Neoplasias/efeitos dos fármacos , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/induzido quimicamente , Moléculas de Adesão Celular/efeitos dos fármacos , Neoplasias Hepáticas/induzido quimicamente , Células-Tronco Neoplásicas/efeitos dos fármacos , Niacinamida/análogos & derivados , Proteína Oncogênica v-akt/fisiologia , Compostos de Fenilureia/efeitos adversos , Proteínas Supressoras de Tumor/fisiologia , Animais , Carcinoma Hepatocelular/classificação , Progressão da Doença , Molécula de Adesão da Célula Epitelial , Humanos , Neoplasias Hepáticas/classificação , Camundongos , Niacinamida/efeitos adversos , Sorafenibe , Proteína 2 do Complexo Esclerose Tuberosa
7.
Cell Res ; 24(3): 359-71, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24323043

RESUMO

The transcription factor NF-κB plays a pivotal role in innate immunity in response to a variety of stimuli, and the coordinated regulation of this pathway determines the proper host responses to extracellular signals. In this study, we identified RACK1 as a novel negative regulator of NF-κB signaling, NF-κB-mediated cytokine induction and inflammatory reactions. RACK1 physically associates with the IKK complex in a TNF-triggered manner. This interaction interferes with the recruitment of the IKK complex to TRAF2, which is a critical step for IKK phosphorylation and subsequent activation triggered by TNF. By modulating the interaction between TRAF2 and IKK, RACK1 regulates the levels of NF-κB activation in response to different intensities of stimuli. Our findings suggest that RACK1 plays an important role in controlling the sensitivity of TNF-triggered NF-κB signaling by regulating IKK activation and provide new insight into the negative regulation of inflammatory reactions.


Assuntos
Proteínas de Ligação ao GTP/metabolismo , Quinase I-kappa B/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Superfície Celular/metabolismo , Fator 2 Associado a Receptor de TNF/metabolismo , Citocinas/metabolismo , Ativação Enzimática/efeitos dos fármacos , Proteínas de Ligação ao GTP/antagonistas & inibidores , Proteínas de Ligação ao GTP/química , Células HEK293 , Células HeLa , Humanos , Quinase I-kappa B/química , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Fosforilação/efeitos dos fármacos , Ligação Proteica , Estrutura Terciária de Proteína , Interferência de RNA , Pequeno RNA não Traduzido/metabolismo , Receptores de Quinase C Ativada , Receptores de Superfície Celular/antagonistas & inibidores , Receptores de Superfície Celular/química , Transdução de Sinais/efeitos dos fármacos , Fator 2 Associado a Receptor de TNF/química , Fator de Necrose Tumoral alfa/farmacologia
8.
J Hepatol ; 59(6): 1255-63, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23867314

RESUMO

BACKGROUND & AIMS: Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC. METHODS: In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo. RESULTS: ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone. CONCLUSIONS: These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Hepatocelular/tratamento farmacológico , Cisplatino/farmacologia , Neoplasias Hepáticas/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Tretinoína/farmacologia , Animais , Antígenos de Neoplasias/fisiologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Moléculas de Adesão Celular/fisiologia , Diferenciação Celular/efeitos dos fármacos , Sinergismo Farmacológico , Molécula de Adesão da Célula Epitelial , Humanos , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Células-Tronco Neoplásicas/citologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo
9.
Asian Pac J Cancer Prev ; 14(6): 3509-14, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23886137

RESUMO

The prognostic value of the fibroblast growth factor-inducible 14 (Fn14) expression in hepatocellular carcinoma (HCC) is unknown. Real-time PCR (RT-PCR), western blot assays and immunohistochemistry analysis were here performed in order to compare Fn14 expressions in paired liver samples of HCC and normal liver tissue. Most of the tumor tissues expressed significantly higher levels of Fn14 compared to adjacent non-tumor tissues, with Fn14High accounting for 54.6% (142/260) of all patients. The Pearson χ(2) test indicated that Fn14 expression was closely associated with serum alpha fetal protein (AFP) (P=0.002) and tumor number (p=0.019). Univariate and multivariate analyses revealed that along with tumor diameter and portal vein tumor thrombosis (PVTT ) type, Fn14 was an independent prognostic factor for both overall survival (OS) (HR=1.398, p=0.008) and recurrence (HR=1.541, p=0.001) rates. Fn14 overexpression HCC correlated with poor surgical outcome, and this molecule may be a candidate biomarker for prognosis as well as a target for therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Fígado/metabolismo , Recidiva Local de Neoplasia/mortalidade , Receptores do Fator de Necrose Tumoral/metabolismo , Biomarcadores Tumorais/genética , Western Blotting , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores do Fator de Necrose Tumoral/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Receptor de TWEAK , Análise Serial de Tecidos
10.
Gastroenterology ; 142(4): 812-823.e15, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22240482

RESUMO

BACKGROUND & AIMS: Dysregulation of Wnt signaling has been involved in gastric tumorigenesis by mechanisms that are not fully understood. The receptor for activated protein kinase C (RACK1, GNB2L1) is involved in development of different tumor types, but its expression and function have not been investigated in gastric tumors. METHODS: We analyzed expression of RACK1 in gastric tumor samples and their matched normal tissues from 116 patients using immunohistochemistry. Effects of knockdown with small interfering RNAs or overexpression of RACK1 in gastric cancer cell lines were evaluated in cell growth and tumor xenograft. RACK1 signaling pathways were investigated in cells and zebrafish embryos using immunoblot, immunoprecipitation, microinjection, and in situ hybridization assays. RESULTS: Expression of RACK1 was reduced in gastric tumor samples and correlated with depth of tumor infiltration and poor differentiation. Knockdown of RACK1 in gastric cancer cells accelerated their anchorage-independent proliferation in soft agar, whereas overexpression of RACK1 reduced their tumorigenicity in nude mice. RACK1 formed a complex with glycogen synthase kinase Gsk3ß and Axin to promote the interaction between Gsk3ß and ß-catenin and thereby stabilized the ß-catenin destruction complex. On stimulation of Wnt3a, RACK1 repressed Wnt signaling by inhibiting recruitment of Axin by Dishevelled 2 (Dvl2). Moreover, there was an inverse correlation between expression of RACK1 and localization of ß-catenin to the cytoplasm/nucleus in human gastric tumor samples. CONCLUSIONS: RACK1 negatively regulates Wnt signaling pathway by stabilizing the ß-catenin destruction complex and act as a tumor suppressor in gastric cancer cells.


Assuntos
Complexo de Sinalização da Axina/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Superfície Celular/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Via de Sinalização Wnt , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Complexo de Sinalização da Axina/genética , Estudos de Casos e Controles , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Proteínas Desgrenhadas , Feminino , Proteínas de Ligação ao GTP/genética , Regulação Neoplásica da Expressão Gênica , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Células HEK293 , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Transplante de Neoplasias , Fosfoproteínas/metabolismo , Interferência de RNA , Receptores de Quinase C Ativada , Receptores de Superfície Celular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Fatores de Tempo , Transfecção , Proteínas Supressoras de Tumor/genética , Via de Sinalização Wnt/genética , Proteína Wnt3A/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , beta Catenina/metabolismo
11.
PLoS One ; 6(6): e21419, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21731740

RESUMO

BACKGROUND: Esophageal Squamous Cell Carcinoma (ESCC) is a major subtype of esophageal cancer causing significant morbility and mortality in Asia. Mechanism of initiation and progression of this disease is unclear. Tumor initiating cells (TICs) are the subpopulation of cells which have the ability to self-renew, as well as, to drive initiation and progression of cancer. Increasing evidence has shown that TICs exist in a variety of tumors. However, the identification and characterization of TICs in esophageal carcinoma has remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: to identify TICs in ESCC, ESCC cell lines including two primary cells were used for screening suitable surface marker. Then colony formation assay, drug resistant assay and tumorigenicity assay in immune deficient mice were used to characterize TICs in ESCC. We found that just the CD44 expression correlated with tumorigenicity in ESCC cell lines. And then induced differentiation of ESCC cells by all-trans retinoic acid treatment led to decreased expression of CD44. The FACS isolated cell subpopulations with high CD44 expression showed increased colony formation and drug resistance in vitro, as well as significantly enhanced tumorigenicity in NOD/SICD mice, as compared to the low expressing CD44 ESCC cells. CONCLUSIONS/SIGNIFICANCE: our study has discovered a novel TIC surface marker, CD44, which can be utilized to enrich efficiently the TICs in ESCC. These findings will be useful for further studies of these cells and exploring therapeutic approaches.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Receptores de Hialuronatos/metabolismo , Células-Tronco Neoplásicas/patologia , Adulto , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Morte Celular/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos
12.
Hepatology ; 53(2): 483-92, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21274870

RESUMO

UNLABELLED: Surgical resection is the first-line treatment for hepatocellular carcinoma (HCC) patients with well-preserved liver function. Nevertheless, the rate of postoperative recurrence at 5 years is as high as 70%, and this gravely jeopardizes the therapeutic outcome. Clearly, new approaches are needed for preventing the relapse of this deadly disease. Taking advantage of a luciferase-labeled orthotopic xenograft model of HCC, we examined the role of sorafenib, the first systemic drug approved for advanced HCC patients, in the prevention of HCC recurrence. We found that sorafenib suppressed the development of postsurgical intrahepatic recurrence and abdominal metastasis and consequently led to prolonged postoperative survival of mice in this model. Furthermore, hyperactivity of extracellular signal-regulated kinase signaling caused by elevated levels of growth factors associated with postoperative liver regeneration enhanced the sensitivity of HCC cells to sorafenib; this provides a plausible explanation for the observation that recurrent tumors are more responsive to growth inhibition by sorafenib. CONCLUSION: Our results strongly suggest that by effectively reducing postoperative recurrence, sorafenib has a potential application in early-stage HCC patients who have undergone hepatectomy with curative intention.


Assuntos
Antineoplásicos/uso terapêutico , Benzenossulfonatos/uso terapêutico , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Metástase Neoplásica/prevenção & controle , Recidiva Local de Neoplasia/prevenção & controle , Piridinas/uso terapêutico , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzenossulfonatos/farmacologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Niacinamida/análogos & derivados , Compostos de Fenilureia , Piridinas/farmacologia , Sorafenibe , Transplante Heterólogo , Resultado do Tratamento
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