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1.
Acta Cir Bras ; 34(12): e201901202, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32049183

RESUMO

PURPOSE: To explore the potential role and unclear molecular mechanisms of vaccarin in wound healing. METHODS: Rats' skin excision model to study the effects of vaccarin on wound healing in vivo . Hematoxylin and eosin staining was performed to evaluate Histopathologic characteristics. Immunohistochemistry was employed to assess the effects of vaccarin in accelerating angiogenesis. Western blot was used to evaluate relative protein expressed levels. RESULTS: Vaccarin could significantly promote wound healing and endothelial cells and fibroblasts proliferation in the wound site. Immunohistochemistry and Western blot studies showed that the nodal proteins and receptor (bFGFR) related to angiogenesis signaling pathway were activated, and the microvascular density in the wound site was markedly higher than that in the control group. CONCLUSIONS: The present study was the first to demonstrate that vaccarin is able to induce angiogenesis and accelerate wound healing in vivo by increasing expressions of p-Akt, p-Erk and p-bFGFR. This process is mediated by MAPK/ERK and PI3K/AKT signaling pathways.


Assuntos
Indutores da Angiogênese/farmacologia , Caryophyllaceae/química , Quinases de Proteína Quinase Ativadas por Mitógeno/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Extratos Vegetais/farmacologia , Cicatrização/efeitos dos fármacos , Animais , Western Blotting , Proliferação de Células/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Imuno-Histoquímica , Masculino , Quinases de Proteína Quinase Ativadas por Mitógeno/análise , Fosfatidilinositol 3-Quinases/análise , Extratos Vegetais/química , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/efeitos dos fármacos , Reprodutibilidade dos Testes , Transdução de Sinais , Fatores de Tempo
2.
Proc Natl Acad Sci U S A ; 115(33): 8388-8393, 2018 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-30061390

RESUMO

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.


Assuntos
Caderinas/fisiologia , Flagelos/metabolismo , Células Ciliadas Auditivas Internas/metabolismo , Precursores de Proteínas/fisiologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Proteínas Adaptadoras de Transporte Vesicular/fisiologia , Animais , Embrião de Galinha , Clatrina/fisiologia , Camundongos , Fosforilação , Transporte Proteico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise
3.
Anticancer Res ; 38(5): 3105-3110, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29715147

RESUMO

BACKGROUND/AIM: The expression of IL-8 and FGFR has been related to prognosis and pathological features in renal cell carcinoma. We investigated the relationship between IL-8 and FGFR and the outcome in metastatic renal cell carcinoma (mRCC) patients. MATERIALS AND METHODS: Clinical data and histological samples of patients affected by mRCC and treated with targeted agents were reviewed. The expression of proteins was assessed using immunohistochemistry. RESULTS: FGFR1, FGFR2, and IL-8 were found to be expressed in 16%, 30%, and 50% of cases, respectively. Significant correlations were found between selected proteins. A lack of expression of FGFR2 and IL8 was found to be correlated with increased progression-free survival (PFS). The survival rate at 24 months was 44%, 38%, and 79% of those expressing both, one, or none of the evaluated proteins, respectively (p=0.047). CONCLUSION: This analysis found a relationship between the expression of IL-8 and FGFR2 in mRCC patients treated with targeted agents.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Idoso , Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Interleucina-8/análise , Interleucina-8/biossíntese , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Estudos Retrospectivos
4.
Curr Comput Aided Drug Des ; 14(3): 191-199, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29663897

RESUMO

BACKGROUND: Melanoma is the most aggressive type of skin cancer. Metastatic melanoma is extremely difficult to treat with current therapy methods such as surgery. On the other hand, it is a good opportunity to develop a radiopharmaceutical using a radionuclide such as Technetium (Tc) for diagnostic and Rhenium (Re) for therapeutic purposes. T3,4BCPP has been be used as a radioimaging agent for melanoma cancers experimentally. The aim of the present research was to design new imidazolylporphyrin derivatives with better selectivity and higher affinity than those of T3,4BCPP by molecular modeling. METHODS: Eight types of Re- and Tc-labeled imidazolylporphyrins were docked to Fibroblast Growth Factor Receptor 1 (FGFR1, PDB ID: 5AM6) using AutoDock 4.2. FGFR1 was simulated by Molecular Dynamic (MD) simulation for 30 ns using NAMD 2.10 at 37 °C. The obtained conformations were then applied in a molecular docking simulation. Dovitinib (natural ligand of FGFR1), Re- and Tc-T3, 4BCPP were used as references. RESULTS: The MD simulation resulted in an RMSD of 3.8 Å. From all the studied imidazolylporphyrin derivatives, Tc-cD3, 4BCPMIP and Re-cD3, 4BCPIP had the best docking parameter. Tc-cD3, 4BCPMIP had a free binding energy of -4.06 kcal/mol, while that of Re-cD3, 4BCPIP was -4.35 kcal/mol. CONCLUSION: It is concluded that cD3,4BCPMIP and cD3,4BCPIP are two potential candidate ligands for a melanoma radiopharmaceutical kit.


Assuntos
Imidazóis/química , Melanoma/diagnóstico , Porfirinas/química , Compostos Radiofarmacêuticos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Rênio/química , Tecnécio/química , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
5.
Sci Rep ; 7(1): 6490, 2017 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-28747655

RESUMO

Skin cancer and its associated treitments can have devastating consequences for survivors; this is particularly true when cancer occurs on the nose. Recent work has applied cell-based tissue engineering (TE) strategies to develop nasal cartilage constructs for reconstruction of the nose. In this study, we have generated human nasal cartilage on a clinically approved collagen scaffold to investigate the donor-to-donor variability of TE cartilage and evaluated strategies to mitigate it. We also evaluated the gene expression of the family of fibroblast growth factor receptors (FGFR1-4) and their association with tissue quality. FGFR 1 was significantly positively correlated with GAG/DNA; a measure of chondrogenic capacity. We implemented two strategies: hypoxic culture and co-culture with mesenchymal stromal cells (MSCs) to increase tissue quality. Total glycosaminoglycan (GAG) content varied significantly between donors initially, with >10-fold difference between the best and worst donor tissue. Our co-culture strategy was able to increase TE construct quality from poor quality donor tissue while supressing hypertrophy relative to MSCs alone. However, no differences were observed with the use of hypoxic culture. Tissues generated using co-culture with MSCs became vascularized and calcified in vivo, demonstrating a non-stable cartilage phenotype in co-culture and MSCs cartilage constructs.


Assuntos
Cartilagens Nasais/crescimento & desenvolvimento , Engenharia Tecidual/métodos , Engenharia Tecidual/normas , Glicosaminoglicanos/análise , Humanos , Cartilagens Nasais/química , Neoplasias Nasais/cirurgia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Procedimentos Cirúrgicos Reconstrutivos/métodos
6.
Mol Carcinog ; 56(11): 2391-2399, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28418088

RESUMO

Phosphorylation of Pyruvate Kinase M2 (PKM2) on Tyr105 by fibroblast growth factor receptor 1 (FGFR1) has been shown to promote its nuclear localization as well as cell growth in lung cancer. Better understanding the regulation of this process would benefit the clinical treatment for lung cancer. Here, it has been found that the adaptor protein receptor for activated PKC kinase (RACK1) formed a complex with FGFR1 and PKM2, and activated the FGFR1/PKM2 signaling. Knocking down the expression of RACK1 impaired the phosphorylation on Tyr105 of PKM2 and inhibited the growth and migration of lung cancer cells, while over-expression of RACK1 in lung cancer cells led to the resistance to Erdafitinib. Moreover, knocking down the expression of RACK1 impaired the tumorigenesis of lung cancer driven by LKB loss and mutated Ras (KrasG12D). Taken together, our study demonstrated the pivotal roles of RACK1 in FGFR1/PKM2 signaling, suggesting FGFR1/RACK1/PKM2 might be a therapeutic target for lung cancer treatment.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Proteínas de Transporte/metabolismo , Proteínas de Ligação ao GTP/metabolismo , Neoplasias Pulmonares/metabolismo , Pulmão/patologia , Proteínas de Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Mapas de Interação de Proteínas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Superfície Celular/metabolismo , Hormônios Tireóideos/metabolismo , Animais , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/análise , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Proteínas de Ligação ao GTP/análise , Humanos , Pulmão/metabolismo , Neoplasias Pulmonares/patologia , Proteínas de Membrana/análise , Camundongos , Proteínas de Neoplasias/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptores de Quinase C Ativada , Receptores de Superfície Celular/análise , Hormônios Tireóideos/análise
7.
Indian J Pathol Microbiol ; 60(4): 593-595, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29323084

RESUMO

Myeloid and lymphoid hematological malignancies with eosinophilia and abnormalities of fibroblast growth factor receptor-1 (FGFR1) result from the formation of abnormal fusion genes that encode constitutively activated tyrosine kinases. The WHO classification (2008) of hematolymphoid neoplasms recognizes a category of myeloid and lymphoid neoplasms with eosinophilia and abnormalities of FGFR1. Here, we present the case of a 30-year-old-woman who was diagnosed with T-lymphoblastic lymphoma from lymph node biopsy and myeloproliferative neoplasm with eosinophilia from bone marrow studies. She was treated with combination chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD regimen) and is on maintenance chemotherapy for the past 2 months. We present this case to create awareness among physicians about this rare condition associated with dual malignancies.


Assuntos
Neoplasias da Medula Óssea/diagnóstico , Neoplasias da Medula Óssea/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Adulto , Antineoplásicos/administração & dosagem , Biópsia , Medula Óssea/patologia , Neoplasias da Medula Óssea/tratamento farmacológico , Eosinofilia/etiologia , Eosinofilia/patologia , Feminino , Histocitoquímica , Humanos , Cariotipagem , Linfonodos/patologia , Microscopia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico
8.
Oncotarget ; 7(52): 87124-87135, 2016 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-27893433

RESUMO

Recent evidence suggests that T-box transcription factor brachyury plays an important role in lung cancer development and progression. However, the mechanisms underlying brachyury-driven cellular processes remain unclear. Here we found that fibroblast growth factor receptor 1/mitogen-activated protein kinase (FGFR1/MAPK) signaling regulated brachyury in lung cancer. Analysis of FGFR1-4 and brachyury expression in human lung tumor tissue and cell lines found that only expression of FGFR1 was positively correlated with brachyury expression. Specific knockdown of FGFR1 by siRNA suppressed brachyury expression and epithelial-mesenchymal transition (EMT) (upregulation of E-cadherin and ß-catenin and downregulation of Snail and fibronectin), whereas forced overexpression of FGFR1 induced brachyury expression and promoted EMT in lung cancer cells. Activation of fibroblast growth factor (FGF)/FGFR1 signaling promoted phosphorylated MAPK extracellular signal-regulated kinase (ERK) 1/2 translocation from cytoplasm to nucleus, upregulated brachyury expression, and increased cell growth and invasion. In addition, human lung cancer cells with higher brachyury expression were more sensitive to inhibitors targeting FGFR1/MAPK pathway. These findings suggest that FGFR1/MAPK may be important for brachyury activation in lung cancer, and this pathway may be an appealing therapeutic target for a subset of brachyury-driven lung cancer.


Assuntos
Proteínas Fetais/fisiologia , Neoplasias Pulmonares/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/fisiologia , Proteínas com Domínio T/fisiologia , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal , Humanos , Sistema de Sinalização das MAP Quinases/fisiologia , Invasividade Neoplásica , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Transdução de Sinais/fisiologia
9.
Oncotarget ; 7(16): 22234-44, 2016 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-26993773

RESUMO

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare, highly malignant, and poorly understood sarcomas. The often poor outcome of MPNST highlights the necessity of identifying prognostic predictors for this aggressive sarcoma. Here, we investigate the role of fibroblast growth factor receptor (FGFR) family members in human MPNSTs. RESULTS: aCGH and bioinformatics analysis identified frequent amplification of the FGFR1 gene. FISH analysis revealed that 26.9% MPNST samples had amplification of FGFR1, with both focal and polysomy patterns observed. IHC identified that FGFR1 protein expression was positively correlated with FGFR1 gene amplification. High expression of FGFR1 protein was associated with better overall survival (OS) and was an independent prognostic predictor for OS of MPNST patients. Additionally, combined expression of FGFR1 and FGFR2 protein characterized a subtype of MPNST with better OS. FGFR4 protein was expressed 82.3% of MPNST samples, and was associated with poor disease-free survival. MATERIALS AND METHODS: We performed microarray-based comparative genomic hybridization (aCGH) profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Medical University Cancer Institute and Hospital. Fluorescence in situ hybridization (FISH) was used to validate the gene amplification detected by aCGH analysis. Another cohort of 63 formalin-fixed paraffin-embedded MPNST samples (including 52 samples for FISH assay) was obtained to explore FGFR1, 2, 3, and 4 protein expression by immunohistochemical (IHC) analysis. CONCLUSIONS: Our integrated genomic and molecular studies provide evidence that FGFRs play different prognostic roles in MPNST.


Assuntos
Biomarcadores Tumorais/análise , Neurilemoma/patologia , Receptores de Fatores de Crescimento de Fibroblastos/biossíntese , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neurilemoma/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/biossíntese , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/biossíntese , Receptores de Fatores de Crescimento de Fibroblastos/análise , Adulto Jovem
10.
Histopathology ; 68(6): 925-30, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26407099

RESUMO

AIMS: Phosphaturic mesenchymal tumour (PMT) is a rare, recently described neoplastic entity. It is characterized by distinct histological features, which often occur together with oncogenic osteomalacia. Recently, a novel FN1-FGFR1 gene fusion has been described in a subset of PMTs. The aim of this study is to characterise the clinicopathological features of two PMTs, with FGFR1 immunohistochemical and cytogenetic analyses. METHODS AND RESULTS: We present two contrasting cases of PMT, one occurring in the sinonasal region, and the other occurring in bone (proximal femur). In the former, local effects, including epistaxis and anosmia, dominated the clinical presentation, whereas the latter case presented with refractory bone pain, muscle weakness, and occult osteomalacia, the cause of which was only identified after 2 years. Both tumours showed characteristic histological features of PMT, including a monomorphic proliferation of round to ovoid cells, osteoclast-like multinucleated giant cells, and areas of 'smudgy' basophilic calcifications. Chromogenic in-situ hybridization showed fibroblast growth factor FGF-23 expression by the sinonasal tumour. By using immunohistochemistry, we also demonstrated, for the first time, FGF receptor 1 (FGFR1) protein overexpression in this tumour, for which FN1-FGFR1 gene fusion was not detected by fluorescence in-situ hybridization. CONCLUSIONS: Our findings indicate that up-regulation of FGFR1 in phosphaturic mesenchymal tumours can occur via mechanisms other than FN1-FGFR1 fusion, raising the possibility of FGFR1 overexpression being a potential common pathway with pathophysiological and therapeutic implications.


Assuntos
Neoplasias Ósseas/patologia , Cavidade Nasal/patologia , Neoplasias Nasais/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Neoplasias de Tecidos Moles/patologia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Análise Citogenética , Epistaxe/etiologia , Humanos , Hipofosfatemia/etiologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Nasais/complicações , Neoplasias Nasais/genética , Dor/etiologia , Neoplasias de Tecidos Moles/complicações , Neoplasias de Tecidos Moles/genética
11.
Int J Clin Exp Pathol ; 8(9): 9760-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26617686

RESUMO

AIM: Non-small cell lung carcinoma is the leading cause of cancer related to death in the world. Squamous cell lung carcinoma (SqCLC) is the second most frequent histological subtype of lung carcinomas. Recently, growth factors, growth factor receptors, and signal transduction system-related gene amplifications and mutations are extensively under investigation to estimate the prognosis and to develop individualized therapies in SqCLC. In this study, besides the signal transduction molecule phosphatidyl inositol-3-phosphate kinase (IP3K) p110α, we explored the expressions of fibroblast growth factor 2 (FGF2) and receptor-1 (FGFR1) in tumor tissue and also their clinical and prognostic significance in patients with early/advanced SqCLC. MATERIALS AND METHODS: From 2005 to 2013, 129 patients (23 early, 106 advanced disease) with a histopathological SqCLC diagnosis were selected from the hospital files of Cukurova University Medical Faculty for this study. Two independent pathologists evaluated FGFR1, FGF2, and PI3K (p110α) expressions in both tumor and stromal tissues from 99 of the patients with sufficient tissue samples, using immunohistochemistry. Considering survival analysis separately for patients with both early and advanced stage diseases, the relationship between the clinical features of the patients and expressions were evaluated by univariate and multivariate analyses. RESULTS: FGFR1 expression was found to be low in 59 (60%) patients and high in 40 (40%) patients. For FGF2; 12 (12%) patients had high, 87 (88%) patients had low expression and for IP3K; 31 (32%) patients had high and 66 (68%) patients had low expressions. In univariate analysis, overall survival (OS) was significantly associated with stage of the disease and the performance status of the patient (P<0.0001 and P<0.001). There was no significant difference in OS of the patients with either low or high expressions of FGFR1, FGF2, and IP3K. When the patients with early or advanced stage disease were separately taken into consideration, the relationship did not differ, either. Any of FGFR1, FGF2 or IP3K expressions was not found predictive for the treatment of early or advanced staged patients. On the other hand, the expressions of both FGFR1 and FGF2 were significantly different with respect to smoking, scar of tuberculosis and scar of radiotherapy (P=0.002; P=0.06 and P=0.05, respectively). DISCUSSION: There has not been identified an effective individualized treatment for SqCLC yet. Therefore, in order to be able to develop such a treatment in the future, it is essential to identify the genetic abnormalities that are responsible for the biological behaviors and carcinogenesis of SqCLC. Although we could not show the prognostic and predictive significance of FGFR1, FGF2 and IP3K expressions in SqCLC, we determined the expression rates of FGFR1, FGF2 and IP3K as a reference for Turkish patients. In conclusion, we want to put some emphasis on the fact that, pulmonary fibrosis which is a late complication of radiotherapy at stage III disease, and the scar of tuberculosis could be associated with FGFR1 and FGF2 expressions.


Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/patologia , Fator 2 de Crescimento de Fibroblastos/biossíntese , Neoplasias Pulmonares/patologia , Fosfatidilinositol 3-Quinases/biossíntese , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/biossíntese , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/mortalidade , Classe I de Fosfatidilinositol 3-Quinases , Feminino , Fator 2 de Crescimento de Fibroblastos/análise , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/análise , Prognóstico , Modelos de Riscos Proporcionais , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise
12.
Eur J Gynaecol Oncol ; 36(5): 506-13, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26513873

RESUMO

PURPOSE: Syndecan-1 (SDC-1) promotes the proliferation of cancer cells and plays a role in angiogenesis by binding to a variety of extracellular effectors. The present study was designed to compare the expression of SDC-1 in the normal ovary and in ovarian tumors, to better understand its roles in the progression of epithelial ovarian carcinoma (EOC). MATERIALS AND METHODS: The expression of SDC- 1, fibroblast growth factor 2 (FGF-2), and FGF receptor 1 (FGFRI) and their transcripts in 65 samples including the normal ovary, benign tumors, borderline ovarian tumors, and EOC was assessed using immunohistochemistry and the reverse transcription-polymerase chain reaction. The influence of FGF-2 on the expression of SDC-1 mRNA syndecan-1 in a human ovarian carcinoma cell line was determined using an FGF-2-neutralizing antibody. RESULTS: SDC-l was not detected in normal ovarian tissue but was present in the epithelial cells of benign or borderline tumors and in ovarian adenocarcinomas. The levels of expression were significantly different in ovarian tissues derived from benign or malignant cases. Coordinate stromal expression of SDC-1 and its mRNA was detected at the original site of the tumor, as well as in metastatic foci in the greater omentum of ovarian adenocarcinomas. FGF-2 reduced the level of expression of SDC-1 mRNA when added exogenously to SKOV3 cells. This effect was abolished in the presence of an FGF-2-neutralizing antibody. CONCLUSION: SDC-l contributes to the role of FGF-2 in proliferation and angiogenesis but may also play a role in the invasive properties of EOC. To the present authors' knowledge, this study is the first to report the presence of distinct patterns ofexpression of SDC-1 in local and metastatic foci in the greater omentum in patients with EOC. These data reinforce the role of the tumor stroma in the invasive properties of ovarian adenocarcinoma and suggest that stromal changes in the expression of SDC-1 may originate from the stroma and contribute to the pathogenesis and metastatic potential of EOC.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/patologia , Sindecana-1/análise , Adulto , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/fisiologia , Carcinoma Epitelial do Ovário , Progressão da Doença , Feminino , Fator 2 de Crescimento de Fibroblastos/análise , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Epiteliais e Glandulares/química , Neoplasias Ovarianas/química , Ovário/química , RNA Mensageiro/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Sindecana-1/genética , Sindecana-1/fisiologia
13.
J Periodontol ; 86(7): 899-905, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25879792

RESUMO

BACKGROUND: Innate and adaptive immunosurveillance mechanisms in response to the normal commensal bacteria can affect periodontal innate defense status. However, it is still unclear how commensal bacteria contribute to the inflammatory responses of junctional epithelium (JE) and periodontal connective tissue (PCT). The aim of the present study is to investigate the contribution of commensal bacteria on inflammatory responses in JE and PCT in mice. METHODS: The periodontal tissue of germ-free (GF) and specific-pathogen-free (SPF) mice were compared at age 11 to 12 weeks (n = 6 per group). In this study, the number of neutrophils and expression of intercellular adhesion molecule (ICAM)-1, fibroblast growth factor receptor (FGFR)-1, matrix metalloproteinase (MMP)-1, and MMP-8 within the JE and the PCT are evaluated. The collagen density was also determined in PCT stained with picrosirius red (PSR). PSR staining combined with or without polarized light microscopy has been used to assess the organization and maturation of collagen matrix. RESULTS: In the present findings, the area of JE in SPF mice was significantly greater than that in GF mice (P <0.05). In addition, the JE and PCT in SPF mice showed greater migration of neutrophils and higher expression of ICAM-1, FGFR-1, MMP-1, and MMP-8 than those in GF mice (P <0.05). Furthermore, the density of collagen in PCT in SPF mice was lower compared to GF mice (P <0.05). CONCLUSION: These results indicate that commensal bacteria induced a low-grade inflammatory state in JE and that such conditions may contribute to degradation of collagen in PCT in mice.


Assuntos
Bactérias/imunologia , Inserção Epitelial/microbiologia , Boca/microbiologia , Periodonto/microbiologia , Simbiose/imunologia , Animais , Compostos Azo , Movimento Celular/imunologia , Colágeno/análise , Colágeno/ultraestrutura , Corantes , Tecido Conjuntivo/imunologia , Tecido Conjuntivo/microbiologia , Inserção Epitelial/imunologia , Vida Livre de Germes , Imunidade Inata/imunologia , Molécula 1 de Adesão Intercelular/análise , Metaloproteinase 13 da Matriz/análise , Metaloproteinase 8 da Matriz/análise , Camundongos , Microscopia de Polarização/métodos , Neutrófilos/imunologia , Periodonto/imunologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Organismos Livres de Patógenos Específicos
14.
Mol Carcinog ; 54(9): 841-52, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24719266

RESUMO

Fibroblast growth factor receptors (FGFRs) are important in malignant progression of several human epithelial tumors. However, little is known about FGFRs in canine or human soft tissue sarcomas. Thus, our aim was to investigate expression of FGFRs and their involvement in cell survival in sarcomas of both species. FGFR1-4 and FGFRL1 transcripts as well as IIIb/IIIc splice variants of FGFR1-3 were evaluated in 3 canine- and 6 human sarcoma cell lines and 19 spontaneous canine sarcomas by SYBRqPCR. FGFR1 protein expression was assessed by immunohistochemistry. Growth inhibitory effects of FGFR1 inhibitor PD166866 and dominant negative recombinant FGFR adenoviral expression constructs (dnFGFR) on tumor cell lines were analyzed. Profiling of multiple FGFR transcripts detected comparable co-expression in most of human and canine sarcoma cell lines and canine tumor specimens. This indicates existence of closely related regulation mechanisms for FGFR expression in sarcomas of both species. FGFR1 with splice variant IIIc was consistently expressed with highest transcript levels. In 88% of the spontaneous tumor samples a heterogeneous FGFR1 protein expression was observed. Significant growth inhibition and cell death was seen after infection with dnFGFR1 in canine and human sarcoma cells, but not with dnFGFR3 and 4. PD166866 showed selective cytotoxicity with IC50 values between 12.1 and 26.4 µM. FGFR1 inhibition blocked ligand-induced tyrosine phosphorylation of ERK1/2 mitogen-activated protein kinase isoforms. This study emphasizes the important role FGFR1, especially splice variant IIIc, likely plays in sarcomas. Inhibitory small molecules could be of potential use for targeted therapy in aggressive sarcomas of both species.


Assuntos
Proteínas Tirosina Quinases/farmacologia , Pirimidinas/farmacologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Sarcoma/genética , Ureia/análogos & derivados , Animais , Linhagem Celular Tumoral , Cães , Regulação Neoplásica da Expressão Gênica , Humanos , Isoformas de Proteínas/análise , Isoformas de Proteínas/genética , Estrutura Terciária de Proteína , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Sarcoma/tratamento farmacológico , Sarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Ureia/farmacologia
15.
J Pathol ; 235(4): 539-45, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25319834

RESUMO

Phosphaturic mesenchymal tumours (PMTs) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour-induced osteomalacia (TIO) through secretion of phosphatonins including fibroblast growth factor 23 (FGF23). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1-FGFR1 fusion gene in three out of four PMTs by next-generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT-PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1-FGFR1 fusion out of an additional 11 PMTs. Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia-inducing FGFR1 fusion genes, which are ligand-independent, the FN1-FGFR1 chimeric protein was predicted to preserve its ligand-binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis.


Assuntos
Biomarcadores Tumorais/genética , Fibronectinas/genética , Fusão Gênica , Hipofosfatemia Familiar/etiologia , Neoplasias de Tecido Conjuntivo/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Western Blotting , Feminino , Fibronectinas/análise , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/química , Neoplasias de Tecido Conjuntivo/complicações , Neoplasias de Tecido Conjuntivo/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Int J Clin Exp Pathol ; 6(12): 2846-54, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24294370

RESUMO

OBJECTIVES: The central issue in this study is to investigate the expression of Sex determining region Y-BOX2 (SOX2) and fibroblast growth factor receptor 1 (FGFR1), evaluate their clinicopathological variables and prognostic significance in small cell lung cancer (SCLC). METHODS: Specimens from 222 SCLC patients and 53 adjacent normal lung tissues were detected by the immunohistochemistry for SOX2 and FGFR1 expression. The relationship between the expression of both markers and survival status was determined. RESULTS: Overexpression of SOX2 and FGFR1 were revealed in SCLC tumors than in normal tissues (P<0.05). SOX2 expression was associated with clinical stage (P=0.014) and lymph node status (P=0.041). Besides, FGFR1 expression was significantly higher in ever smokers (P=0.030) and late stage SCLC (P=0.005). SOX2, FGFR1 and TNM stage were independent prognostic factors for overall survival (OS) and Recurrence-free survival (RFS) by multivariate analysis. In stage I patients, only overexpression of SOX2, but not of FGFR1, predicted poor OS (0.027) and RFS (P=0.013). According to the expression of SOX2 and FGFR1, patients were categorized into three groups. Patients with elevated expression of both markers belonged to the group with the shortest RFS (P<0.0001) and OS (P<0.0001). CONCLUSIONS: Increased expression of SOX2 and FGFR1 may be available as poor prognostic indicators in SCLC patients.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias Pulmonares/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Fatores de Transcrição SOXB1/análise , Carcinoma de Pequenas Células do Pulmão/química , Adulto , Idoso , Distribuição de Qui-Quadrado , Intervalo Livre de Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estadiamento de Neoplasias , Razão de Chances , Modelos de Riscos Proporcionais , Fatores de Risco , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Tempo , Regulação para Cima
17.
Stomatologija ; 15(4): 111-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24589633

RESUMO

OBJECTIVE. To investigate cleft disordered tissue in children with cleft palate and cleft lip with or without alveolar clefting for detection of local tissue growth factors and growth factor receptors and compare findings. Design. Morphological analysis of human tissue. Patients. Three groups were studied: 14 patients with cleft palate at the age from eight months to 18 years and two months, 12 patients with cleft lip with or without alveolar clefting in the age from four months to 15 years and four months and 11 control patients. RESULTS. In general, cleft palate disordered tissue showed more prominent expression of BMP2/4 (z=3.574; p=0.0004) and TGFß (z=2.127; p=0.033), while expression of TGFBR3 significantly higher was only in connective tissue (z=3.822; p=0.0001). Cleft lip affected tissue showed significantly pronounced expression of FGFR1 in general as well as separately in epithelium. CONCLUSIONS. The marked and statistically significant expression of BMP 2/4 in cleft palate disordered soft tissue probably is delayed, but still proliferation and differentiation as well as tissue, especially, bone remodeling contributing signal. Cleft palate affected tissue show more prominent expression of TGFß, still the weak regional expression of TGFß type III receptors prove the disordered tissue growth and changed TGFß signalling pathway in postnatal pathogenesis. In general, expression of TGFß, BMP 2/4 and FGFR1 is significantly different, giving evidence to the involvement of these mentioned factors in the cleft severity morphopathogenesis.


Assuntos
Fenda Labial/patologia , Fissura Palatina/patologia , Peptídeos e Proteínas de Sinalização Intercelular/análise , Receptores de Fatores de Crescimento/análise , Adolescente , Proteína Morfogenética Óssea 2/análise , Proteína Morfogenética Óssea 4/análise , Remodelação Óssea/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células , Criança , Pré-Escolar , Fenda Labial/metabolismo , Fissura Palatina/metabolismo , Células do Tecido Conjuntivo/metabolismo , Células do Tecido Conjuntivo/patologia , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Lactente , Microvasos/metabolismo , Microvasos/patologia , Morfogênese/fisiologia , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Proteoglicanas/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptores de Fatores de Crescimento Transformadores beta/análise , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/análise
18.
J Cell Biol ; 197(6): 801-17, 2012 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-22665522

RESUMO

FGF-10 and its receptors, FGFR1 and FGFR2, have been implicated in breast cancer susceptibility and progression, suggesting that fibroblast growth factor (FGF) signaling may be co-opted by breast cancer cells. We identify a novel pathway downstream of FGFR1 activation, whereby the receptor is cleaved and traffics to the nucleus, where it can regulate specific target genes. We confirm Granzyme B (GrB) as the protease responsible for cleavage and show that blocking GrB activity stopped FGFR1 trafficking to the nucleus and abrogates the promigratory effect of FGF stimulation. We confirm the in vivo relevance of our findings, showing that FGFR1 localized to the nucleus specifically in invading cells in both clinical material and a three-dimensional model of breast cancer. We identify target genes for FGFR1, which exert significant effects on cell migration and may represent an invasive signature. Our experiments identify a novel mechanism by which FGF signaling can regulate cancer cell behavior and provide a novel therapeutic target for treatment of invasive breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Núcleo Celular/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Divisão Celular , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Imunofluorescência , Humanos , Transporte Proteico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética
19.
Anal Biochem ; 424(2): 137-9, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22387389

RESUMO

Here we present a highly efficient protocol for on-the-resin coupling of fluorescent dyes or other functional groups to the N-termini of synthetic peptides prior to cleavage and deprotection. The protocol avoids expensive preactivated dyes and instead employs carboxylated dyes activated by large amounts of coupling reagents. The protocol was used to label peptides with low reactivity such as long hydrophobic peptides and peptides with strong tendencies to form sterically shielding structures or aggregates in solution. In all cases, the yields far exceeded those from commercially available preactivated compounds.


Assuntos
Peptídeos/química , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/química , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Coloração e Rotulagem/métodos , Sequência de Aminoácidos , Etilaminas/química , Corantes Fluorescentes , Humanos , Interações Hidrofóbicas e Hidrofílicas , Proteínas Imobilizadas/análise , Proteínas Imobilizadas/química , Dados de Sequência Molecular , Compostos Organofosforados/química , Peptídeos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/análise
20.
J Vasc Res ; 49(3): 249-59, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22433836

RESUMO

OBJECTIVE: Related transcriptional enhancer factor 1 (RTEF-1) is a key transcriptional regulator in endothelial function. In this study, we investigated a possible role for RTEF-1 in the regulation of microvascular relaxation and the underlying mechanism involved. Activation of fibroblast growth factor receptor 1 (FGFR1) by FGFs increases vasodilation, although transcriptional control of the molecular mechanisms underlying FGFR1 is still unclear. MATERIALS AND METHODS: We demonstrated that RTEF-1 stimulated FGFR1 expression at the transcriptional level, specifically an area including Sp1 elements, as evidenced by promoter assays. Additionally, RTEF-1 increased FGFR1 mRNA and protein expression in vitro and in VE-cadherin-promoted RTEF-1 (VE-Cad/RTEF-1) transgenic mice, whereas RTEF-1 siRNA blocked the upregulation of FGFR1 expression. Furthermore, increased endothelial-dependent microvessel relaxation was observed in the coronary arteries of VE-Cad/RTEF-1 mice, and increased proliferation was observed in RTEF-1-overexpressing cells, both of which correlated to increased FGF/FGFR1 signaling and endothelial nitric oxide synthase (eNOS) upregulation. Our results indicate that RTEF-1 acts as a transcriptional stimulator of FGFR1 and is involved in FGF pathways by increasing microvessel dilatation via eNOS. CONCLUSIONS: These findings suggest that RTEF-1 plays an important role in FGFR1- stimulated vasodilatation. Understanding the effect of RTEF-1 in microvessel relaxation may provide beneficial knowledge in improving treatments in regards to ischemic vascular disorders.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Endotélio Vascular/fisiologia , Microvasos/fisiologia , Proteínas Musculares/fisiologia , Fatores de Transcrição/fisiologia , Vasodilatação , Animais , Bovinos , Proliferação de Células , Células Cultivadas , Humanos , Óxido Nítrico Sintase Tipo III/fisiologia , Regiões Promotoras Genéticas , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/análise , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais
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