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1.
Cancer Med ; 13(5): e6958, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38466034

RESUMO

INTRODUCTION: Approximately 30% of individuals with advanced EC have unsatisfactory prognosis. Evidence suggests that TPX2 is frequently upregulated in malignancies and related to cancer progression. Its role and pathological mechanism in EC need further research. METHODS: GSEA and TPX2 expression, GO, KEGG, and prognostic analyses were performed with TCGA data by bioinformatic approaches. Relationships between TPX2 expression and clinicopathological parameters were investigated immunohistochemically and statistically. shRNA and overexpression plasmids were constructed and transfected into AN3CA and Ishikawa cells to evaluate phenotypic changes and injected into nude mouse axillae. Coimmunoprecipitation and chromatin immunoprecipitation were used to identify interacting proteins and promoter-binding sequences. Changes in TPX2 expression were identified by Western blotting and RT-qPCR. RESULTS: TPX2 expression was significantly higher in EC tissues than in normal tissues in TCGA and in-house specimens (all p < 0.001). In survival analysis, high TPX2 expression was associated with poor prognosis (p = 0.003). TPX2 overexpression stimulated cancer cell proliferation, promoted the G0-G1-to-G2/M transition, enhanced invasion and migration, and accelerated tumor growth in nude mice. TPX2 regulated the CX3CR1/CXCL10 chemokine pathway and activated the PI3K/Akt signaling pathway. Sp1 negatively regulated TPX2 expression, affecting the malignant progression of endometrial cancer cells by coupling the CX3CR1/CXCL10 chemokine pathway to the PI3K/Akt signaling pathway. CONCLUSION: TPX2 could be a prognostic biomarker for EC and play an important role in the CX3CR1/CXCL10 chemokine pathway and PI3K/Akt pathway via Sp1.


Assuntos
Quimiocina CXCL10 , Neoplasias do Endométrio , Animais , Camundongos , Feminino , Humanos , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , Camundongos Nus , Neoplasias do Endométrio/genética , Receptor 1 de Quimiocina CX3C , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Ciclo Celular/genética
2.
Pharmacology ; 107(7-8): 398-405, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35526525

RESUMO

INTRODUCTION: Chemoresistance remains the main cause of treatment failure in cervical cancer and novel therapeutic strategies are required. Cobimetinib, a potent yet selective inhibitor of MEK1 and 2, is currently used to treat melanoma clinically. In this work, we identified cobimetinib as a promising candidate for treating cervical cancer. METHODS: The in vitro and in vivo efficacies of cobimetinib were examined using cervical cancer cell cultures and xenograft mouse model. Its combination with paclitaxel was analyzed using the combination index. Immunoblotting was performed on MAPK and ERK pathways. RESULTS: Cobimetinib displays a potent anti-cervical cancer activity in a panel of cell lines regardless of cellular origin and HPV presence, and its combination with paclitaxel is synergistic in inhibiting cervical cancer cells. This is achieved by the growth inhibition and caspase-dependent apoptosis induction, through inhibiting MAPK/ERK activation. In addition, paclitaxel activates ERK in cervical cancer cells, and this can be reversed by cobimetinib. We finally confirm the efficacy of cobimetinib alone and its combination with paclitaxel in the cervical cancer xenograft mouse model. DISCUSSION/CONCLUSION: Our preclinical findings will accelerate the initialization of clinical trials to use combination of cobimetinib and paclitaxel for treating cervical cancer. Our work also emphasizes the therapeutic value of targeting MAPK/ERK to overcome chemoresistance in cervical cancer.


Assuntos
Azetidinas , Neoplasias do Colo do Útero , Animais , Apoptose , Azetidinas/farmacologia , Azetidinas/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Paclitaxel/farmacologia , Piperidinas/farmacologia , Piperidinas/uso terapêutico , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo
3.
Lancet Digit Health ; 4(3): e179-e187, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35216752

RESUMO

BACKGROUND: Ultrasound is a critical non-invasive test for preoperative diagnosis of ovarian cancer. Deep learning is making advances in image-recognition tasks; therefore, we aimed to develop a deep convolutional neural network (DCNN) model that automates evaluation of ultrasound images and to facilitate a more accurate diagnosis of ovarian cancer than existing methods. METHODS: In this retrospective, multicentre, diagnostic study, we collected pelvic ultrasound images from ten hospitals across China between September 2003, and May 2019. We included consecutive adult patients (aged ≥18 years) with adnexal lesions in ultrasonography and healthy controls and excluded duplicated cases and patients without adnexa or pathological diagnosis. For DCNN model development, patients were assigned to the training dataset (34 488 images of 3755 patients with ovarian cancer, 541 442 images of 101 777 controls). For model validation, patients were assigned to the internal validation dataset (3031 images of 266 patients with ovarian cancer, 5385 images of 602 with benign adnexal lesions), external validation datasets 1 (486 images of 67 with ovarian cancer, 933 images of 268 with benign adnexal lesions), and 2 (1253 images of 166 with ovarian cancer, 5257 images of 723 benign adnexal lesions). Using these datasets, we assessed the diagnostic value of DCNN, compared DCNN with 35 radiologists, and explored whether DCNN could augment the diagnostic accuracy of six radiologists. Pathological diagnosis was the reference standard. FINDINGS: For DCNN to detect ovarian cancer, AUC was 0·911 (95% CI 0·886-0·936) in the internal dataset, 0·870 (95% CI 0·822-0·918) in external validation dataset 1, and 0·831 (95% CI 0·793-0·869) in external validation dataset 2. The DCNN model was more accurate than radiologists at detecting ovarian cancer in the internal dataset (88·8% vs 85·7%) and external validation dataset 1 (86·9% vs 81·1%). Accuracy and sensitivity of diagnosis increased more after DCNN-assisted diagnosis than assessment by radiologists alone (87·6% [85·0-90·2] vs 78·3% [72·1-84·5], p<0·0001; 82·7% [78·5-86·9] vs 70·4% [59·1-81·7], p<0·0001). The average accuracy of DCNN-assisted evaluations for six radiologists reached 0·876 and were significantly augmented when they were DCNN-assisted (p<0·05). INTERPRETATION: The performance of DCNN-enabled ultrasound exceeded the average diagnostic level of radiologists matched the level of expert ultrasound image readers, and augmented radiologists' accuracy. However, these observations warrant further investigations in prospective studies or randomised clinical trials. FUNDING: National Key Basic Research Program of China, National Sci-Tech Support Projects, and National Natural Science Foundation of China.


Assuntos
Aprendizado Profundo , Neoplasias Ovarianas , Adolescente , Adulto , China , Feminino , Humanos , Neoplasias Ovarianas/diagnóstico por imagem , Estudos Prospectivos , Estudos Retrospectivos , Ultrassonografia/métodos
4.
Oxid Med Cell Longev ; 2022: 8548461, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35069980

RESUMO

Cervical cancer (CC) is one of the most common malignancies in females, with high prevalence and mortality globally. Despite advances in diagnosis and therapeutic strategies developed in recent years, CC is still a major health burden worldwide. The molecular mechanisms underlying the development of CC need to be understood. In this study, we aimed to demonstrate the role of lncRNA SNHG15 in CC progression. Using qRT-PCR, we determined that lncRNA SNHG15 is highly expressed in CC tumor tissues and cells. lncRNA SNHG15 knockdown also reduces the tumorigenic properties of CC in vitro, as determined using the MTT, EdU, flow cytometry, and transwell assays. Using bioinformatics analysis, RNA pull-down, ChIP, and luciferase reporter assays, we verified the molecular mechanisms of lncRNA SNHG15 in CC progression and found that lncRNA SNHG15 expression in CC cells is transcriptionally regulated by SOX12; moreover, lncRNA SNHG15 promotes CC progression via the miR-4735-3p/HIF1a axis. This study can provide a potential target for CC diagnosis or therapeutic strategies in the future.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição SOXC/metabolismo , Neoplasias do Colo do Útero/genética , Carcinogênese , Feminino , Humanos
5.
Bioengineered ; 12(2): 10183-10193, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34872446

RESUMO

As the second most common cancer among women, cervical cancer is a huge threat to their health all over the world. Integral membrane protein 2A (ITM2A), a member of the Type II Integral Membrane protein (ITM2) family, has been reported to act as a tumor suppressor in breast cancer and ovarian cancer. Moreover, the low expression of ITM2A was associated with cervical adenocarcinoma. However, the function of ITM2A in drug resistance in cervical cancer remains unclear. Here, we used bioinformatics methods to screen differentially expressed genes (DEGs) closely related to chemotherapeutic relapse cervical carcinoma. ITM2A is downregulated in cervical tumor tissues and is associated with poor survival. Furthermore, ITM2A is also downregulated in cervical cancer cells with cisplatin resistance. Overexpression of ITM2A increases the cisplatin sensitivity of cervical cancer cells. Mechanically, ITM2A upregulation mediates the sensitivity of cervical cancer cell through Notch signaling pathway. Our study suggests that ITM2A may serve as a target in mediating cisplatin-resistant cervical cancer.


Assuntos
Proteínas de Membrana/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/metabolismo , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Regulação para Baixo/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Proteínas de Membrana/genética , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Transdução de Sinais/efeitos dos fármacos
7.
Cancer Lett ; 498: 130-141, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33129959

RESUMO

Long noncoding RNAs act essential regulators in cervical cancer progression. Our study aimed to investigate the underlying function and molecular mechanisms of LINC00657 in cervical cancer. QRT-PCR results indicated that LINC00657 was significantly decreased in cervical cancer. Gain-and loss-of-function experiments were performed in SiHa and HeLa. Functional assays demonstrated that LINC00657 inhibited cervical cancer cell growth, migration and invasion. Moreover, miR-20a-5p was confirmed as a target of LINC00657. Furthermore, miR-20a-5p promoted the development of cervical cancer via targeting RUNX3. DR5 acts as a vital promoter in activating NK cells and is a downstream target of RUNX3. We found that LINC00657 overexpression promoted the cytotoxic activity of NK cells via regulating RUNX3/DR5 axis. Therefore, LINC00657 suppressed cervical cancer progression via inducing miR-20a-5p/RUNX3/DR5 mediated NK cell tolerance. In conclusion, LINC00657 was identified as a novel tumor-suppressor in cervical cancer and could function as a potential therapeutic target for clinical treatment.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias do Colo do Útero/genética , Animais , Apoptose/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Camundongos Nus , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Neoplasias do Colo do Útero/patologia
8.
BMC Infect Dis ; 20(1): 642, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32873233

RESUMO

BACKGROUND: Evidence suggested that vaginal microbiome played a functional role in the progression of cervical lesions in female infected by HPV. This study aimed at evaluating the influence of common vaginal infection on the carcinogenicity of high risk HPV (hr-HPV). METHODS: From January 15, 2017 to December 31, 2017, 310,545 female aged at least 30 years old had been recruited for cervical cancer screening from 9 clinical research centers in Central China. All the recruited participants received hr-HPV genotyping for cervical cancer screening and vaginal microenvironment test by a high vaginal swab. Colposcopy-directed biopsy was recommended for female who were infected with HPV 16 and HPV 18, and other positive hr-HPV types through test had undertaken triage using liquid-based cytology, cases with the results ≥ ASCUS among them were referred to colposcopy directly, and cervical tissues were taken for pathology examination to make clear the presence or absence of other cervical lesions. RESULTS: Among 310,545 female, 6067 (1.95%) were tested with positive HPV 16 and HPV 18, 18,297 (5.89%) were tested with other positive hr-HPV genotypes, cervical intraepithelial neoplasia (CIN) 1, CIN 2, CIN 3 and invasive cervical cancer (ICC) were detected in 861 cases, 377 cases, 423 cases, and 77 cases, respectively. Candida albicans and Gardnerella were not associated with the detection of cervical lesions. Positive trichomonas vaginitis (TV) was correlated with hr-HPV infection (p < 0.0001). Co-infection with TV increased the risk of CIN 1 among female infected with hr-HPV (OR 1.18, 95% CI: 1.42-2.31). Co-infection with TV increased the risk of CIN 2-3 among female infected with HPV 16 (OR 1.71, 95% CI: 1.16-2.53). CONCLUSIONS: Co-infection of TV and HPV 16 is a significant factor for the detection of cervical lesions.


Assuntos
Coinfecção/complicações , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Infecções por Papillomavirus/complicações , Vaginite por Trichomonas/complicações , Trichomonas vaginalis/isolamento & purificação , Displasia do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Adulto , China/epidemiologia , Coinfecção/diagnóstico , Colposcopia , Estudos Transversais , Citodiagnóstico , Detecção Precoce de Câncer/métodos , Feminino , Genótipo , Humanos , Pessoa de Meia-Idade , Infecções por Papillomavirus/diagnóstico , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Fatores de Risco , Vaginite por Trichomonas/diagnóstico , Vaginite por Trichomonas/parasitologia , Neoplasias do Colo do Útero/diagnóstico , Neoplasias do Colo do Útero/virologia , Displasia do Colo do Útero/diagnóstico , Displasia do Colo do Útero/virologia
9.
Oncol Lett ; 17(5): 4742, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30944660

RESUMO

[This retracts the article DOI: 10.3892/ol.2016.4607.].

10.
J Cell Physiol ; 234(10): 18985-18993, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30932200

RESUMO

NEAT1 is an important tumor oncogenic gene in various tumors. Nevertheless, its involvement remains poorly studied in cervical cancer. Our study explored the functional mechanism of NEAT1 in cervical cancer. NEAT1 level in several cervical cancer cells was quantified and we found NEAT1 was greatly upregulated in vitro. NEAT1 knockdown inhibited cervical cancer development through repressing cell proliferation, colony formation, capacity of migration, and invasion and also inducing the apoptosis. For another, microRNA (miR)-133a was downregulated in cervical cancer cells and NEAT1 negatively modulated miR-133a expression. Subsequently, we validated that miR-133a functioned as a potential target of NEAT1. Meanwhile, SOX4 is abnormally expressed in various cancers. SOX4 was able to act as a downstream target of miR-133a and silencing of SOX4 can restrain cervical cancer progression. In addition, in vivo assays were conducted to prove the role of NEAT1/miR-133a/SOX4 axis in cervical cancer. These findings implied that NEAT1 served as a competing endogenous RNA to sponge miR-133a and regulate SOX4 in cervical cancer pathogenesis. To sum up, it was implied that NEAT1/miR-133a/SOX4 axis was involved in cervical cancer development.


Assuntos
MicroRNAs/genética , RNA Longo não Codificante/genética , Fatores de Transcrição SOXC/genética , Neoplasias do Colo do Útero/genética , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Células HeLa , Humanos , Neoplasias do Colo do Útero/patologia
11.
Oncol Lett ; 15(6): 10063-10069, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29928375

RESUMO

Cervical cancer is the second most common type of cancer in females worldwide. It has been demonstrated that microRNAs (miRs) serve important roles in the occurrence and development of various types of cancer, including cervical cancer. The results of the present study revealed that miR-197 was downregulated in cervical cancer tissues and cell lines. Restoration of miR-197 expression significantly inhibited cell viability and invasion of cervical cancer. Additionally, forkhead box M1 (FOXM1) was identified as a direct target gene of miR-197. Bioinformatic analysis revealed that FOXM1 was a potential target gene of miR-197. Luciferase reporter assay, reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that miR-197 decreased FOXM1 expression through direct binding to its 3'-untranslated region. Furthermore, the effects of FOXM1 underexpression were comparable with the effects induced by miR-197 overexpression in cervical cancer cells, suggesting that FOXM1 acted as a downstream effector in miR-197-mediated proliferation and invasion of cervical cancer cells. The results of the present study suggested that miR-197 inhibited growth and metastasis of cervical cancer by directly targeting FOXM1.

12.
Gynecol Oncol ; 149(1): 181-187, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29525275

RESUMO

Long non-coding RNAs (lncRNAs), which have little or no protein-coding capacity, caught a particular interest since their potential roles in the cancer paradigm. As the most common cancer in women, cervical squamous cell carcinoma remains one of the leading causes of deaths from cancer. However, limited evidence is available to determine the role of lncRNAs in the prognosis of cervical squamous cell carcinoma. In this study, we collected lncRNA expression profiling to identify prognosis related lncRNAs for cervical squamous cell carcinoma from TCGA database. In addition, we developed a 15-lncRNA signature based risk score to comprehensively assess the prognostic function of lncRNA. Furthermore, we performed a ROC analysis to identify the optimal cut-off point for classification risk level of the patients. Univariate Cox regression models were used to assess the association between lncRNAs and prognosis of patients with cervical squamous cell carcinoma. A 15-lncRNA based risk score was developed based on the Cox co-efficient of the individual lncRNAs. The prognostic value of this risk score was validated in the complete set and internal testing set. In summary, a 15-lncRNA expression signature (BAIAP2-AS1, RP11-203J24.8, LINC01133, RP1-7G5.6, RP11-147L13.15, SERHL, CTC-537E7.3, RP11-440L14.1, RP11-131N11.4, ILF3-AS1, RP11-80H18.4, RP11-1096G20.5, CTD-2192J16.26, RP11-621L6.3, and RP11-571M6.18) were identified and validated which can predict cervical cancer patient survival. The potential functions of this 15-lncRNA expression signature and individual lncRNAs as prognostic targets of cervical cancer were revealed by this study. Furthermore, these findings may have important implications in the understanding of the potential therapeutic method for the cervical squamous cell carcinoma patients.


Assuntos
Carcinoma de Células Escamosas/genética , RNA não Traduzido/genética , Neoplasias do Colo do Útero/genética , Sequência de Bases , Feminino , Humanos , Prognóstico
13.
Oncol Lett ; 12(1): 93-96, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27347106

RESUMO

The aim of the present study was to investigate the effect and mechanism of different concentrations of aspirin in inhibiting the ovarian cancer of p53N236S gene knock-in mice. In total, 28 male p53S mice, with an age range of 4-6 weeks and weight of 20-25 g were selected. The animals were transplanted with SKOV3 cells to establish subdermal human ovarian cancer. The mice were randomly divided into different groups according to the aspirin concentrations (mmol/l) used, i.e., 0, 1, 2 and 3. Subsequently, intraperitoneal injection was performed once every two days for 3 weeks. The tumor volume, lifetime, tumor cell proliferation inhibition rates, caspase-3 protein and bcl-2 protein expression of the four groups were analyzed and compared. Following aspirin treatment for 1, 2 and 3 weeks, the tumor volume of the 3 mmol/l aspirin group was significantly smaller than the other groups (P<0.05). The higher concentration of aspirin led to a smaller tumor size (P<0.05). The cell proliferation inhibition rate of the 3 mmol/l aspirin group was significantly larger than that of other groups (P<0.05). The relative expression level of caspase-3, bcl-2 protein of the 3 mmol/l aspirin group was significantly improved and reduced, respectively. In conclusion, aspirin can inhibit the growth of ovarian cancer of p53S rats due to its upregulation of the expression of caspase-3 protein and downregulation of the expression of bcl-2 protein.

14.
Transpl Int ; 27(10): 1077-85, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24810904

RESUMO

Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Necrostatin-1 (Nec-1) is a small molecule capable of inhibiting RIP1 kinase activity and attenuates inflammation-mediated tissue injury. In our study, hearts of C57Bl/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipients. We found that Nec-1 decreased cardiomyocyte necrosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by Nec-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with Nec-1 administration and the cardiac allograft survival in Nec-1-treated animals was significantly prolonged (MST = 90 days in IR + Nec-1 group, P < 0.05 as compared with IR group, MST = 83.5 days). Nec-1 treatment attenuated ROS generation and increased expression of NOS2 and COX-2. The expression of Hmgb1, IL-23, and IL-17A were also decreased with Nec-1 administration. Furthermore, the decreased TnT expression induced by Nec-1 was abrogated with exogenous Hmgb1 administration. In conclusion, Nec-1 played a protective role in cardiomyocyte IR injury, and this was associated with inhibited Hmgb1-IL-23/IL-17 pathway.


Assuntos
Transplante de Coração/efeitos adversos , Imidazóis/farmacologia , Indóis/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/prevenção & controle , Proteína HMGB1/imunologia , Proteína HMGB1/metabolismo , Transplante de Coração/métodos , Marcação In Situ das Extremidades Cortadas , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Interleucina-23/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Musculares , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e Especificidade , Transplante Heterotópico , Troponina T/metabolismo
15.
Inflammation ; 37(5): 1444-52, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24619454

RESUMO

In order to understand how tumor cells can escape immune surveillance mechanisms and thus develop antitumor therapies, it is critically important to investigate the mechanisms by which the immune system interacts with the tumor microenvironment. In our current study, wild-type mice are inoculated with melanoma cell line B16-F10 (1 × 10(6)/mouse) and treated with anti-IL-7R antibody or recombined mouse IL-7 (rmIL-7). Growth of melanoma cell line B16-F10 was significantly inhibited in anti-IL-7R antibody-treated mice and markedly promoted in rmIL-7-treated mice compared with that in control. A decreased number of myeloid-derived suppressor cells (MDSCs) and γδ cells in tumor tissues were detected from anti-IL-7R antibody-treated mice. Next, administration of the anti-IL-7R antibody significantly blocked the enrichment in IL-17(+) γδ cells in tumor. Moreover, in our further experiment, promoted melanoma development induced by rmIL-7 was abrogated with p-Stat3 inhibitor. The increased proportion and absolute number of IL-17-producing γδ27(-) cell induced by rmIL-7 were also abolished with the p-Stat3 inhibitor administration, and the suppressed melanoma development induced by anti-IL-7R antibody treatment was reversed with additional use of Ad-IL-17. In conclusion, IL-7/IL-7R-Stat3-IL-17 pathway promotes melanoma growth, and inhibition of IL-7/IL-7R-Stat3-IL-17 pathway may contribute to tumor growth in murine models of melanoma.


Assuntos
Interleucina-17/antagonistas & inibidores , Interleucina-17/imunologia , Melanoma Experimental/imunologia , Melanoma Experimental/prevenção & controle , Receptores de Interleucina-7/antagonistas & inibidores , Receptores de Interleucina-7/imunologia , Linfócitos T/imunologia , Animais , Autoanticorpos/administração & dosagem , Linhagem Celular Tumoral , Interleucina-17/biossíntese , Melanoma Experimental/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
16.
Inflammation ; 37(2): 573-80, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24234226

RESUMO

Ischemia reperfusion (IR) injury is a major issue in cardiac transplantation and inflammatory processes play a major role in myocardial IR injury. Netrin-1 is a laminin-related protein identified as a neuronal guidance cue and netrin-1 expressed outside the nervous system inhibits migration of leukocytes in vitro and in vivo and attenuates inflammation-mediated tissue injury. In our study, hearts of C57BL/6 mice were flushed and stored in cold Bretschneider solution for 8 h and then transplanted into syngeneic recipient. We found that netrin-1 decreased cardiomyocyte apoptosis and recruitment of neutrophils and macrophages. Troponin T (TnT) production on 24 h after myocardial IR injury was reduced by netrin-1 administration. Cardiac output at 60 mmHg of afterload pressure was significantly increased in hearts with netrin-1 administration (IR + Netrin-1: 59.9 ± 5.78 ml/min; IR: 26.2 ± 4.3 ml/min; P < 0.05). Netrin-1 treatment increased expression of the alternatively activated macrophage (AAM) markers arginase-1 (Arg-1) and mannose receptor (MR) and promoted proliferator-activated receptor γ (PPARγ) expression in cardiac allograft. Furthermore, decreased TnT expression and reduced allograft infiltration of neutrophils and monocytes/macrophages by netrin-1 was abolished with addition of PPARγ antagonist. In conclusion, netrin-1 attenuates cardiac IR injury and generates AAM which contributes to the protective effect of netrin-1.


Assuntos
Transplante de Coração/efeitos adversos , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miócitos Cardíacos/efeitos dos fármacos , Fatores de Crescimento Neural/farmacologia , Substâncias Protetoras/farmacologia , Proteínas Supressoras de Tumor/farmacologia , Transferência Adotiva , Animais , Apoptose/efeitos dos fármacos , Arginase/metabolismo , Biomarcadores/metabolismo , Citoproteção , Modelos Animais de Doenças , Hemodinâmica/efeitos dos fármacos , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/transplante , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Netrina-1 , Infiltração de Neutrófilos/efeitos dos fármacos , PPAR gama/metabolismo , Receptores de Superfície Celular/metabolismo , Troponina T/metabolismo
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