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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 31(4): 1171-1178, 2023.
Artigo em Chinês | MEDLINE | ID: mdl-37551494

RESUMO

OBJECTIVE: To explore molecular mechanisms by which umbilical cord-derived mesenchymal stem cells suppress the development of GVHD after bone marrow hematopoietic stem cell transplantation. METHODS: A mouse model of aGVHD was constructed after bone marrow hematopoietic stem cell transplantation, and the umbilical cord-derived mesenchymal stem cells were cultured, and then injected into the aGVHD mouse model, so as to investigate its prophylactic efficacy. Prophylactic effect of the exosomes isolated from umbilical cord-derived mesenchymal stem cells on aGVHD mice was assessed. Sequencing analysis of miRNA from exosomes was performed. RESULTS: aGVHD model was successfully constructed after hematopoietic stem cell transplantation. By injecting umbilical cord-derived mesenchymal stem cells into the GVHD mouse model, it was found that the treatment significantly prolonged survival time of mice compared to the untreated group. Injection exosomes derived from umbilical cord-derived mesenchymal stem cells into the GVHD mouse model significantly prolonged the survival time of mice compared to the untreated group. High-throughput sequencing data showed that microRNA such as miR-21 in exosomes isolated from umbilical cord-derived mesenchymal stem cells, which mainly affected the signaling pathways such as cell adhesion, RNA degradation. CONCLUSION: The umbilical cord-derived mesenchymal stem cells can prevent the occurrence of aGVHD after HSCT, which is mediate by MicroRNA in the exosomes derived from umbilical cord-derived mesenchymal stem cells.

3.
Onco Targets Ther ; 12: 8779-8787, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695433

RESUMO

PURPOSE: To investigate the predictive capability of clinical parameters for long-term chemotherapy benefits among stage IIIB-IV non-squamous non-small cell lung cancer (NSCLC) patients without sensitive mutations. PATIENTS AND METHODS: We investigated the clinical features of 206 stage IIIB-IV non-squamous NSCLC patients without sensitive mutations and assessed their predictive value for disease control rate (DCR) at 6 and 12 months post-treatment. RESULTS: Seventy-two patients received docetaxel and platinum-based chemotherapy while 134 received pemetrexed and platinum-based chemotherapy. The 6-month and 12-month DCR were 33 (45.8%) and 6 (8.3%) in the docetaxel group and 69 (51.5%) and 19 (14.2%) in the pemetrexed group, respectively. Univariate Cox regression revealed that age, sex, smoking history, adrenal gland metastasis, stage IV disease, neutrophil-to-lymphocyte ratio (NLR), and serum albumin were associated with unfavorable progression-free survival (PFS). Age, stage IV disease, and NLR were identified as independent predictors of PFS using multivariate analysis. NLR was the only parameter that could predict 3-month and 6-month DCRs. NLR and age were able to predict 12-month DCR, with NLR presenting a larger area under the curve. Kaplan-Meier curves demonstrated that patients with NLR > 2.231 displayed significantly reduced long-term disease control. The group with higher NLR had more male patients, lower ALB levels, and serum sodium levels as well as higher platelet counts. CONCLUSION: NLR was an independent predictor of long-term chemotherapy benefits among non-squamous NSCLC patients without sensitive mutations. Patients with lower NLR were optimal candidates for chemotherapy. Patients with high NLR may receive alternative treatments or be included in clinical trials.

4.
Int J Biol Sci ; 15(9): 1802-1815, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523184

RESUMO

Deletion of Chromosome 3p is one of the most frequently detected genetic alterations in nasopharyngeal carcinoma (NPC). We reported the role of a novel 3p26.3 tumor suppressor gene (TSG) CHL1 in NPC. Down-regulation of CHL1 was detected in 4/6 of NPC cell lines and 71/95 (74.7%) in clinical tissues. Ectopic expressions of CHL1 in NPC cells significantly inhibit colony formation and cell motility in functional study. By up-regulating epithelial markers and down-regulating mesenchymal markers CHL1 could induce mesenchymal-epithelial transition (MET), a key step in preventing tumor invasion and metastasis. CHL1 could also cause the inactivation of RhoA/Rac1/Cdc42 signaling pathway and inhibit the formation of stress fiber, lamellipodia, and filopodia. CHL1 could co-localize with adhesion molecule Integrin-ß1, the expression of CHL1 was positively correlated with Integrin-ß1 and another known tumor suppressor gene (TSG) Merlin. Down-regulation of Integrin-ß1 or Merlin was significantly correlated with the poor survival rate of NPC patients. Further mechanistic studies showed that CHL1 could directly interact with integrin-ß1 and link to Merlin, leading to the inactivation of integrin ß1-AKT pathway. In conclusion, CHL1 is a vital tumor suppressor in the carcinogenesis of NPC.


Assuntos
Moléculas de Adesão Celular/metabolismo , Integrina beta1/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Neurofibromina 2/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Western Blotting , Moléculas de Adesão Celular/genética , Pontos de Checagem do Ciclo Celular/genética , Pontos de Checagem do Ciclo Celular/fisiologia , Linhagem Celular , Movimento Celular/genética , Movimento Celular/fisiologia , Metilação de DNA/genética , Metilação de DNA/fisiologia , Imunofluorescência , Humanos , Imunoprecipitação , Carcinoma Nasofaríngeo/genética , Regiões Promotoras Genéticas/genética , Interferência de RNA , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
5.
PLoS One ; 14(5): e0217124, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31095636

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0056959.].

6.
Theranostics ; 8(1): 185-198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29290801

RESUMO

Background and Aims: Esophageal squamous cell carcinoma (ESCC), a major histologic subtype of esophageal cancer, is increasing in incidence, but the genetic underpinnings of this disease remain unexplored. The aim of this study is to identify the recurrent genetic changes, elucidate their roles and discover new biomarkers for improving clinical management of ESCC. Methods: Western blotting and immunohistochemistry were performed to detect the expression level of RHCG. Bisulfite genomic sequencing (BGS) and methylation-specific PCR (MSP) were used to study the methylation status in the promoter region of RHCG. The tumor-suppressive effect of RHCG was determined by both in-vitro and in-vivo assays. Affymetrix cDNA microarray was used to identify the underlying molecular mechanism. Results:RHCG was frequently downregulated in ESCCs, which was significantly correlated with poor differentiation (P = 0.001), invasion (P = 0.003), lymph node metastasis (P = 0.038) and poorer prognosis (P < 0.001). Demethylation treatment and bisulfite genomic sequencing analyses revealed that the downregulation of RHCG in both ESCC cell lines and clinical samples was associated with its promoter hypermethylation. Functional assays demonstrated that RHCG could inhibit clonogenicity, cell motility, tumor formation and metastasis in mice. Further study revealed that RHCG could stabilize IκB by decreasing its phosphorylation, and subsequently inhibit NF-κB/p65 activation by blocking the nuclear translocation of p65, where it acted as a transcription regulator for the upregulation of MMP1 expression. Conclusions: Our results support the notion that RHCG is a novel tumor suppressor gene that plays an important role in the development and progression of ESCC.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Neoplasias Esofágicas/metabolismo , Metaloproteinase 1 da Matriz/metabolismo , Glicoproteínas de Membrana/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Proteínas de Transporte de Cátions/genética , Linhagem Celular Tumoral , Metilação de DNA/genética , Metilação de DNA/fisiologia , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas do Esôfago , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Metástase Linfática/genética , Masculino , Metaloproteinase 1 da Matriz/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
7.
Oncotarget ; 8(39): 65957-65968, 2017 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-29029485

RESUMO

Frizzled (FZD) proteins are receptors for secreted WNT proteins and play a critical role in the malignant progression of various cancers. However, the role of human FZD family members in esophageal squamous cell carcinoma (ESCC) was rarely investigated. In this study, we found that the FZD7 gene was the most commonly up-regulated FZD member in ESCC cell lines compared with other FZDs. TMA studies further validated that FZD7 protein was up-regulated in 165 of 252 (65.5%) informative ESCC patients and significantly correlated with poor overall survival (P=0.001). Additionally, multivariate Cox regression analysis showed that FZD7 overexpression was an independent prognostic factor for ESCC patients. Ectopic expression of FZD7 could promote ESCC cell metastasis both in vitro and in vivo. Under WNT3A stimulation, FZD7 was able to induce the nuclear translocation of ß-catenin and activate the downstream targets of WNT/ß-catenin signaling, as well as promote epithelial-mesenchymal transition (EMT) potential in ESCC cells. Our study demonstrated for the first time that FZD7 contributes to the malignant progression of ESCC and represents a novel prognostic marker and a potential therapeutic target for ESCC patients.

8.
Proc Natl Acad Sci U S A ; 114(23): E4631-E4640, 2017 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-28533408

RESUMO

Like many complex human diseases, esophageal squamous cell carcinoma (ESCC) is known to cluster in families. Familial ESCC cases often show early onset and worse prognosis than the sporadic cases. However, the molecular genetic basis underlying the development of familial ESCC is mostly unknown. We reported that SLC22A3 is significantly down-regulated in nontumor esophageal tissues from patients with familial ESCC compared with tissues from patients with sporadic ESCCs. A-to-I RNA editing of the SLC22A3 gene results in its reduced expression in the nontumor esophageal tissues of familial ESCCs and is significantly correlated with lymph node metastasis. The RNA-editing enzyme ADAR2, a familial ESCC susceptibility gene identified by our post hoc genome-wide association study, is positively correlated with the editing level of SLC22A3 Moreover, functional studies showed that SLC22A3 is a metastasis suppressor in ESCC, and deregulation of SLC22A3 facilitates cell invasion and filopodia formation by reducing its direct association with α-actinin-4 (ACTN4), leading to the increased actin-binding activity of ACTN4 in normal esophageal cells. Collectively, we now show that A-to-I RNA editing of SLC22A3 contributes to the early development and progression of familial esophageal cancer in high-risk individuals.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Edição de RNA , Actinina/metabolismo , Adenosina Desaminase/genética , Adenosina Desaminase/metabolismo , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/secundário , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Regulação para Baixo , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/secundário , Carcinoma de Células Escamosas do Esôfago , Esôfago/citologia , Esôfago/metabolismo , Técnicas de Silenciamento de Genes , Estudo de Associação Genômica Ampla , Humanos , Metástase Linfática/genética , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Proteínas de Transporte de Cátions Orgânicos/deficiência , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Fatores de Risco
9.
Oncotarget ; 8(26): 42300-42313, 2017 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-28404945

RESUMO

Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Adulto , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Células Estromais/metabolismo , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Ativador de Plasminogênio Tipo Uroquinase/genética
10.
Carcinogenesis ; 38(1): 94-104, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27879277

RESUMO

Reprogramming of intracellular metabolism is common in liver cancer cells. Understanding the mechanisms of cell metabolic reprogramming may present a new basis for liver cancer treatment. In our previous study, we reported that a novel oncogene eukaryotic translation initiation factor 5A2 (EIF5A2) promotes tumorigenesis under hypoxic condition. Here, we aim to investigate the role of EIF5A2 in cell metabolic reprogramming during hepatocellular carcinoma (HCC) development. In this study, we reported that the messenger RNA (mRNA) level of EIF5A2 was upregulated in 59 of 105 (56.2%) HCC clinical samples (P = 0.015), and EIF5A2 overexpression was significantly associated with shorter survival time of patients with HCC (P = 0.021). Ectopic expression of EIF5A2 in HCC cell lines significantly promoted cell growth and accelerated glucose utilization and lipogenesis rates. The high rates of glucose uptake and lactate secretion conferred by EIF5A2 revealed an abnormal activity of aerobic glycolysis in HCC cells. Several key enzymes involved in glycolysis including glucose transporter type 1 and 2, hexokinase 2, phosphofructokinase liver type, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2 isoform, phosphoglycerate mutase 1 and lactate dehydrogenase A were upregulated by overexpression of EIF5A2. Moreover, EIF5A2 showed positive correlations with FASN and ACSS2, two key enzymes involved in the fatty acid de novo biosynthetic pathway, at both protein and mRNA levels in HCC. These results indicated that EIF5A2 may regulate fatty acid de novo biosynthesis by increasing the uptake of acetate. In conclusion, our findings demonstrate that EIF5A2 has a critical role in HCC cell metabolic reprogramming and may serve as a prominent novel therapeutic target for liver cancer treatment.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/metabolismo , Glucose/metabolismo , Lipogênese , Neoplasias Hepáticas/metabolismo , Redes e Vias Metabólicas , Fatores de Iniciação de Peptídeos/metabolismo , Proteínas de Ligação a RNA/metabolismo , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Reprogramação Celular , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Glicólise , Humanos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Fatores de Iniciação de Peptídeos/genética , Prognóstico , Proteínas de Ligação a RNA/genética , Taxa de Sobrevida , Fator de Iniciação de Tradução Eucariótico 5A
11.
Nat Commun ; 7: 13568, 2016 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-27924820

RESUMO

Non-CG methylation has been associated with stemness regulation in embryonic stem cells. By comparing differentially expressed genes affected by non-CG methylation between tumour and corresponding non-tumour tissues in oesophageal squamous cell carcinoma (OSCC), we find that Integrin α7 (ITGA7) is characterized as a potential cancer stem cell (CSC) marker. Clinical data show that a high frequency of ITGA7+ cells in OSCC tissues is significantly associated with poor differentiation, lymph node metastasis and worse prognosis. Functional studies demonstrate that both sorted ITGA7+ cells and ITGA7 overexpressing cells display enhanced stemness features, including elevated expression of stemness-associated genes and epithelial-mesenchymal transition features, as well as increased abilities to self-renew, differentiate and resist chemotherapy. Mechanistic studies find that ITGA7 regulates CSC properties through the activation of the FAK-mediated signalling pathways. As knockdown of ITGA7 can effectively reduce the stemness of OSCC cells, ITGA7 could be a potential therapeutic target in OSCC treatment.


Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Cadeias alfa de Integrinas/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Antígenos CD/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Humanos , Cadeias alfa de Integrinas/metabolismo , Metástase Linfática , Camundongos Endogâmicos NOD , Camundongos SCID , Interferência de RNA , Transplante Heterólogo , Carga Tumoral/genética
12.
Adv Mater ; 28(35): 7680-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27374972

RESUMO

A bottom-up synthetic strategy is developed to fabricate a highly porous wave-superposed perchlorate-doped polypyrrole nanocoating on nickel nanotube arrays. The delicate nanostructure and the unique surface chemistry synergistically endow the obtained electrode with revealable pseudocapacitance, large operating potential window, and excellent cycling stability, which are highly promising for both asymmetric and symmetric supercapacitors.

13.
Dalton Trans ; 45(26): 10620-9, 2016 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-27273611

RESUMO

Heterodimetallic Ru-Fe complexes [(tppz)(PPh3)2RuL](ClO4) (L = C[triple bond, length as m-dash]CFc, [](ClO4); C[triple bond, length as m-dash]C-C6H4-C[triple bond, length as m-dash]CFc), [](ClO4); C[triple bond, length as m-dash]C-C6H4-C6H4-C[triple bond, length as m-dash]CFc, [](ClO4)) were synthesized by the reactions of [(tppz)(PPh3)2RuCl](ClO4) (tppz = 2,3,5,6-tetrakis(2-pyridyl)pyrazine) with ferrocence-acetylide ligands and characterized by ESI-MS, and (1)H and (31)P NMR spectroscopies. The structure of [](PF6) was determined by X-ray crystallography. The electrochemical studies show that compounds [](ClO4)-[](ClO4) possess two widely separated anodic peaks, ascribable to one-electron oxidation of Fc and Ru(II), respectively. This assignment is further corroborated by the results of UV-vis-NIR, XPS, and theoretical calculation studies. Compound [](ClO4) exhibits significant RuFe metal-metal interactions across the Ru-C[triple bond, length as m-dash]C-Fc backbone. As revealed by electrochemical, spectroscopic and theoretical computational studies, one-electron oxidized species [](ClO4)2 is between the electronically delocalized and valence-trapped state and shows a typical Robin-Day class II mixed-valence behavior.

14.
Carcinogenesis ; 37(3): 320-332, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26785734

RESUMO

Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy; its mechanisms of development and progression are poorly understood. By high-throughput transcriptome sequencing (RNA-Seq) profiling of three pairs of primary ESCCs and their corresponding non-tumorous tissues, we identified that prostate stem cell antigen (PSCA), a gene that encodes a glycosylphosphatidylinositol-anchored protein, is significantly downregulated in ESCC. Here, we reported decreased expression of PSCA in 188/218 (86.2%) of primary ESCC cases and was negatively regulated by its transcription factor sex-determining region Y-box5 that was significantly associated with the poor differentiation (P = 0.003), increased lymph node metastasis (P < 0.0001), advanced stage (P = 0.007), and disease-specific survival (P < 0.0001), but not associated with the recently reported transcrible rs2294008 (C > T) polymorphism in ESCC. Functional studies showed that PSCA could arrest cell cycle progression and promote cell differentiation independent of the start codon polymorphism. Further mechanistic studies revealed that retinoblastoma 1-inducible coiled-coil 1 (RB1CC1), a key signaling node to regulate cellular proliferation and differentiation, interacted specifically with PSCA in ESCC cells. Binding of PSCA and RB1CC1 in cytoplasm resulted in stabilization and translocation of RB1CC1 into nucleus, thereby activating key factors involved in cell cycle arrest and differentiation. Collectively, our data provide a novel molecular mechanism for the tumor suppressor role of PSCA and may help design effective therapy targeting PSCA-RB1CC1 pathway to control esophageal cancer growth and differentiation.


Assuntos
Antígenos de Neoplasias/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/patologia , Proteínas de Neoplasias/metabolismo , Transporte Proteico/fisiologia , Proteínas Tirosina Quinases/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Proteínas Relacionadas à Autofagia , Imunoprecipitação da Cromatina , Ensaio de Desvio de Mobilidade Eletroforética , Carcinoma de Células Escamosas do Esôfago , Proteínas Ligadas por GPI/metabolismo , Xenoenxertos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Nus , Análise Serial de Tecidos
15.
Am J Med Genet B Neuropsychiatr Genet ; 168B(3): 170-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25656957

RESUMO

MicroRNAs (miRNA, miR) have been implicated as promising blood-based biomarkers for schizophrenia patients. This study aimed to clinically validate miRNA as potential schizophrenia biomarkers. Plasma levels of 10 miRNAs were analyzed using qPCR in a cohort of 61 schizophrenia patients and 62 normal controls, as well as 25 patients particularly selected for a six-week antipsychotic treatment course. Positive And Negative Syndrome Scale (PANSS), Global Assessment Scale (GAS) and Clinical Global Impression (CGI) were administered to assess the clinical symptoms. The results demonstrated that a panel of miRNAs consisting of miR-30e, miR-181b, miR-34a, miR-346 and miR-7 had significantly increased expression levels with significant combined diagnostic value (AUC:0.713; sensitivity:35.5%; specificity:90.2%). In response to pharmacological treatment, expression levels of miR-132, miR-181b, miR-432 and miR-30e were significantly decreased. In addition, the improvement of clinical symptomatology was significantly correlated with the changes of miR-132, miR-181b, miR-212 and miR-30e expression levels. Furthermore, the decreases of plasma levels of miR-132 and miR-432 were significantly greater in high-effect subgroup than those in low-effect subgroup after six-week treatment course. We conclude that miR-30e, miR-181b, miR-34a, miR-346 and miR-7 combined as a panel are potentially useful non-invasive biomarkers for schizophrenia diagnosis. Markers miR-132, miR-181b, miR-30e and miR-432 are potential indicators for symptomatology improvements, treatment responses and prognosis for schizophrenia patients.


Assuntos
Antipsicóticos/uso terapêutico , Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , MicroRNAs/genética , Esquizofrenia/genética , Adolescente , Adulto , Biomarcadores Tumorais/sangue , Estudos de Casos e Controles , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Adulto Jovem
16.
Oncotarget ; 5(22): 11576-87, 2014 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-25344912

RESUMO

Esophageal cancer is the sixth most common cause of cancer-related deaths worldwide. Novel therapeutic intervention is urgently needed for this deadly disease. The functional role of PI3K/AKT pathway in esophageal cancer is little known. In this study, our results from 49 pairs of human esophageal tumor and normal specimens demonstrated that AKT was constitutively active in the majority (75.5%) of esophageal tumors compared with corresponding normal tissues. Inhibition of the PI3K/AKT pathway with specific inhibitors, wortmannin and LY294002, significantly reduced Bcl-xL expression, induced caspase-3-dependent apoptosis, and repressed cell proliferation and tumor growth in vitro and in vivo without obvious toxic effects. Moreover, significantly higher expression level of p-AKT was observed in fluorouracil (5-FU)-resistant esophageal cancer cells. Inactivation of PI3K/AKT pathway markedly increased the sensitivity and even reversed acquired resistance of esophageal cancer cells to chemotherapeutic drugs in vitro. More importantly, the resistance of tumor xenografts derived from esophageal cancer cells with acquired 5-FU resistance to chemotherapeutic drugs was significantly abrogated by wortmannin treatment in animals. In summary, our data support PI3K/AKT as a valid therapeutic target and strongly suggest that PI3K/AKT inhibitors used in conjunction with conventional chemotherapy may be a potentially useful therapeutic strategy in treating esophageal cancer patients.


Assuntos
Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/metabolismo , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Androstadienos/química , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Cromonas/química , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/química , Feminino , Fluoruracila/química , Humanos , Camundongos , Camundongos Nus , Morfolinas/química , Transplante de Neoplasias , Transdução de Sinais , Wortmanina
17.
Carcinogenesis ; 35(5): 1154-61, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24510112

RESUMO

Here, we report the characterization of a candidate tumor suppressor gene leucine-rich glioma inactivated 1 (LGI1) in human esophageal squamous cell carcinoma (ESCC). Downregulation of LGI1 has been detected in approximately 50% of primary ESCCs, which was significantly associated with advanced clinical stage (P < 0.001), lymph node metastasis (P < 0.001), tumor invasion (P = 0.009) and poor disease-specific survival (P < 0.001). Functional studies found that LGI1 could inhibit cell growth, clonogenicity, cell motility and tumor formation in nude mice. Mechanistic investigations suggested that LGI1 acted through extracellular signal-regulated kinase (ERK1/2) signaling to downregulate matrix metalloproteinase (MMP)-3 expression and subsequently suppressed tumor metastasis. Taken together, our study revealed that LGI1 plays an important tumor suppressive role in the development and progression of ESCC, with possible application in clinics as a biomarker and a potential new therapeutic target.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patologia , Regulação Neoplásica da Expressão Gênica , Proteínas/genética , Adulto , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Movimento Celular/genética , Regulação para Baixo , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/mortalidade , Carcinoma de Células Escamosas do Esôfago , Feminino , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Sistema de Sinalização das MAP Quinases , Masculino , Metaloproteinase 3 da Matriz/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Interferência de RNA , Proteínas Supressoras de Tumor/genética
18.
PLoS One ; 8(3): e56959, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23554857

RESUMO

PURPOSE: Gastric cancer remains one of the leading causes of cancer death worldwide. Patients usually present late with local invasion or metastasis, for which there are no effective therapies available. Following previous studies that identified the adhesion molecule Cadherin-17(CDH17) as a potential marker for gastric carcinoma, we performed proof-of-principle studies to develop rational therapeutic approaches targeting CDH17 for treating this disease. METHODS: Immunohistochemistry was used to study the expression of CDH17 in 156 gastric carcinomas, and the relationship between survival and CDH17 expression was studied by multivariate analyses. The effect of RNA interference-mediated knockdown of CDH17 on proliferation of gastric carcinoma cell lines was examined in vitro and in vivo, as well as the effects on downstream signaling by immunoblotting. RESULTS: CDH17 was consistently up-regulated in human gastric cancers, and overall survival in patients with CDH17 upregulation was poorer than in those without expression of this gene (5 yrs overall survival rate 29.0% vs. 45.0%, P<0.01). Functional assays demonstrated that CDH17 knockdown inhibited cell proliferation, adhesion, migration, invasion, clonogenicity and induce G0/G1 arrest. In mice, shRNA-mediated CDH17 knockdown markedly inhibits tumor growth; intratumoral injection of CDH17 shRNAs results in significant antitumor effects on transplanted tumor models. The antitumor mechanisms underlying CDH17 inhibition involve inactivation of Wnt/ß-catenin signaling. CONCLUSION: Our results identify CDH17 as a biomarker of gastric carcinoma and attractive therapeutic target for this aggressive malignancy.


Assuntos
Biomarcadores Tumorais/biossíntese , Caderinas/biossíntese , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/metabolismo , Neoplasias Gástricas/metabolismo , Proteínas Wnt , Via de Sinalização Wnt , beta Catenina , Adulto , Animais , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Caderinas/antagonistas & inibidores , Caderinas/genética , Adesão Celular/genética , Movimento Celular/genética , Intervalo Livre de Doença , Feminino , Pontos de Checagem da Fase G1 do Ciclo Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Invasividade Neoplásica , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/genética , Fase de Repouso do Ciclo Celular/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Ensaios Antitumorais Modelo de Xenoenxerto
19.
Mol Cell Biochem ; 375(1-2): 105-13, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23291919

RESUMO

Paroxetine is a widely used antidepressant in clinic. Besides its role in inhibition of serotonin reuptake, resent studies indicate that the increase of hippocampal neurogenesis is also involved in its pharmacology. However, only limited data are available in this regard and its effect on the hippocampus-derived neural stem cell (NSCs) has not been well elucidated. In present study, we utilized hippocampus-derived NSCs from fetal rats to investigate the direct effect of paroxetine on the neurogenesis of NSCs and explore the possible cellular and molecular mechanisms. The results showed that paroxetine not only promoted the proliferation of NSCs, but also promoted NSCs to differentiate into neurons other than glial cells. In addition, the elevated protein levels of phosphorylated ERK1/2, Bcl-2, and brain-derived neurotrophic factor were also observed after paroxetine was administered. Furthermore, the proliferative effect and promotion of NSCs differentiating predominantly into neurons of paroxetine was inhibited by U0126, an ERK1/2 phosphorylation inhibitor. In conclusion, these data indicate that paroxetine can promote neurogenesis of neural stem cells, and this effect might be mediated by ERK1/2 signal pathways.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Hipocampo/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/efeitos dos fármacos , Paroxetina/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Butadienos/farmacologia , Proliferação de Células , Células Cultivadas , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feto/citologia , Proteína Glial Fibrilar Ácida/metabolismo , Sistema de Sinalização das MAP Quinases , Células-Tronco Neurais/efeitos dos fármacos , Nitrilas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/fisiologia , Tubulina (Proteína)/metabolismo , Regulação para Cima
20.
Carcinogenesis ; 34(2): 454-63, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23125220

RESUMO

Nasopharyngeal carcinoma (NPC) is a type of head and neck cancer with significantly high prevalence in Southern China. Unlike other head and neck cancers, mutations or deletions of tumor suppressor genes in NPC are not common. Recently, downregulation of tumor suppressor genes expression by microRNA (miRNA) is increasingly recognized as an important mechanism of nasopharyngeal tumorigenesis. In this study, we reported that microRNA-144 (miR-144) was frequently upregulated in NPC specimens and cell lines. Repression of miR-144 significantly decreased cell proliferation, clonogenicity, migration, invasion and tumor formation in nude mice, while restoring miR-144 in miR-144-attenuated NPC cells exhibited a strong tumorigenic role. Further, we found that miR-144 was inversely correlated with the tumor suppressor gene phosphatase and tensin homolog (PTEN) in NPC specimens and cell lines, and then we identified PTEN as a direct target of miR-144 in NPC cell lines. PTEN downregulation in miR-144-attenuated cells could increase cell growth, migration and invasion. Mechanistic investigations revealed that miR-144 suppressed the expression of PTEN to increase the expression of pAkt and cyclin D1 to promote G(1)-phase transition and decrease E-cadherin to promote migration and invasion. Taken together, we provide compelling evidence that miR-144 functions as an onco-miRNA in NPC, and its oncoeffects are mediated chiefly by repressing PTEN expression to activate the PI3K/Akt pathway.


Assuntos
Movimento Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Nasofaríngeas/patologia , Nasofaringe/metabolismo , PTEN Fosfo-Hidrolase/antagonistas & inibidores , Adulto , Idoso , Animais , Apoptose , Western Blotting , Carcinoma , Estudos de Casos e Controles , Adesão Celular , Ciclo Celular , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/genética , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas
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