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1.
BMC Cancer ; 19(1): 963, 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619201

RESUMO

BACKGROUND: Overexpression of fibroblast growth factor receptor 3 (FGFR3) has been linked to tumor progression in many types of cancer. The role of FGFR3 in melanoma remains unclear. In this study, we aimed to uncover the role of FGFR3 in the growth and metastasis of melanoma. METHODS: FGFR3 knockdown and overexpression strategies were employed to investigate the effects of FGFR3 on colony formation, cell apoptosis, proliferation, migration, and in vitro invasion, along with the growth and metastasis of melanoma in a xenografts mouse model. The protein expression levels of extracellular signal-regulated kinase (ERK), protein kinase B (AKT), epidermal growth factor receptor (EGFR), and epithelial-mesenchymal transition (EMT) markers were determined by Western blot analysis. RESULTS: The mRNA expression of FGFR3 was higher in melanoma tissues than normal healthy tissues. FGFR3 expression in cutaneous malignant melanoma (CMM) tissues was positively correlated with the Breslow thickness and lymph node metastasis. In A357 cells, knockdown of the FGFR3 gene decreased the colony formation ability, cell proliferation, invasion, and migration, but increased the caspase 3 activity and the apoptosis rate; overexpression of FGFR3 increased the colony formation ability, cell proliferation, invasion, and migration, but decreased the caspase 3 activity and apoptosis rates. FGFR3 knockdown also upregulated E-cadherin, downregulated N-cadherin and vimentin, and decreased the phosphorylation levels of ERK, AKT, and EGFR. In the MCC xenografts mice, knockdown of FGFR3 decreased tumor growth and metastasis. CONCLUSIONS: FGFR3, which is highly expressed in CMM tissues, is correlated with increased Breslow thickness and lymph node metastasis. FGFR3 promotes melanoma growth, metastasis, and EMT behaviors, likely by affecting the phosphorylation levels of ERK, AKT, and EGFR.


Assuntos
Transição Epitelial-Mesenquimal/genética , Sistema de Sinalização das MAP Quinases , Melanoma/metabolismo , Melanoma/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Animais , Antígenos CD/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Caderinas/metabolismo , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Receptores ErbB/metabolismo , Xenoenxertos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica/genética , Fosforilação , Transfecção , Vimentina/metabolismo
2.
Int J Mol Sci ; 20(18)2019 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-31540114

RESUMO

Radiotherapy is an essential component of cancer therapy. Carbon ion radiotherapy (CIRT) promises to improve outcomes compared with standard of care in many cancers. Nevertheless, clinicians often observe in-field recurrence after CIRT. This indicates the presence of a subset of cancers that harbor intrinsic resistance to CIRT. Thus, the development of methods to identify and sensitize CIRT-resistant cancers is needed. To address this issue, we analyzed a unique donor-matched pair of clinical specimens: a treatment-naïve tumor, and the tumor that recurred locally after CIRT in the same patient. Exon sequencing of 409 cancer-related genes identified enrichment of somatic mutations in FGFR3 and FGFR4 in the recurrent tumor compared with the treatment-naïve tumor, indicating a pivotal role for FGFR signaling in cancer cell survival through CIRT. Inhibition of FGFR using the clinically available pan-FGFR inhibitor LY2874455 sensitized multiple cancer cell lines to carbon ions at 3 Gy (RBE: relative biological effectiveness), the daily dose prescribed to the patient. The sensitizer enhancement ratio was 1.66 ± 0.17, 1.27 ± 0.09, and 1.20 ± 0.18 in A549, H1299, and H1703 cells, respectively. Our data indicate the potential usefulness of the analytical pipeline employed in this pilot study to identify targetable mutations associated with resistance to CIRT, and of LY21874455 as a sensitizer for CIRT-resistant cancers. The results warrant validation in larger cohorts.


Assuntos
Radioterapia com Íons Pesados , Recidiva Local de Neoplasia/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/genética , Células A549 , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/radioterapia , Feminino , Ontologia Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Indazóis/farmacologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Projetos Piloto , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 4 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Transdução de Sinais , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/radioterapia
3.
Exp Mol Pathol ; 111: 104297, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31476288

RESUMO

We present a case report that entails prenatal ultrasonography, postnatal characteristics, and molecular genetic analysis of a newborn who presented with thanatophoric dysplasia type I (TDI) with a mutation in the fibroblast growth factor receptor 3 gene (FGFR3). A malformed newborn with tachypnea, delivered by caesarean at the gestational age of 39 weeks, was the first child of nonconsanguineous parents by a spontaneous pregnancy. Features in prenatal ultrasonography and postnatal radiography were consistent with the diagnosis of TDI, presenting with short body length (38 cm, <3rd percentile), redundant skin folds, a narrow thorax with a bust of 29.5 cm (3-5th percentile), and macrocephaly with a head circumference of 36 cm (>97th percentile). The proposita had postnatal dyspnea and unfortunately died of respiratory failure at the age of 13 days. Molecular genetic analysis revealed a mutation of c.2419 T > C (p. Ter807Arg) (X807R) in FGFR3. Live-born infants with TDI are exceedingly rare, and we hereby report a newborn with a c.2419 T > C mutation in FGFR3, emphasizing phenotype with clinical characteristics and ultrasonographic and X-ray findings, to raise awareness about the heterogeneous patterns of TD.


Assuntos
Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/deficiência , Displasia Tanatofórica/genética , Displasia Tanatofórica/patologia , Adulto , Sequência de Aminoácidos , Sequência de Bases , Feminino , Idade Gestacional , Humanos , Recém-Nascido , Fenótipo , Gravidez , Prognóstico , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética
4.
BMC Med Genet ; 20(1): 149, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31477042

RESUMO

BACKGROUND: Rotator cuff disease is a widespread musculoskeletal pathology and a major cause of shoulder pain. Studies on familial predisposition suggest that genetic plays a role in the pathogenesis of rotator cuff disease. Several genes are responsible for rotator cuff disease. The aim of this study was to perform a systematic review on genetic association between rotator cuff disease and genes variations. METHODS: A systematic review of the literature was performed, in accordance with the PRISMA guidelines. PubMed, Medline, CINAHL, Cochrane, Embase and Google Scholar databases were searched comprehensively using the keywords: "Rotator cuff", "Gene", "Genetic", "Predisposition", "Single-nucleotide polymorphism" and "Genome-wide association". RESULTS: 8 studies investigating genes variations associated with rotator cuff tears were included in this review. 6 studies were case-control studies on candidate genes and 2 studies were GWASs. A significant association between SNPs and rotator cuff disease was found for DEFB1, FGFR1, FGFR3, ESRRB, FGF10, MMP-1, TNC, FCRL3, SASH1, SAP30BP, rs71404070 located next to cadherin8. Contradictory results were reported for MMP-3. CONCLUSION: Further investigations are warranted to identify complete genetic profiles of rotator cuff disease and to clarify the complex interaction between genes, encoded proteins and environment. This may lead to individualized strategies for prevention and treatment of rotator cuff disease. LEVEL OF EVIDENCE: Level IV, Systematic Review.


Assuntos
Variação Genética , Estudo de Associação Genômica Ampla , Lesões do Manguito Rotador/genética , Caderinas/genética , Bases de Dados Factuais , Fator 10 de Crescimento de Fibroblastos/genética , Humanos , Metaloproteinase 1 da Matriz/genética , Proteínas Nucleares/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores Estrogênicos/genética , Receptores Imunológicos/genética , Manguito Rotador , Tenascina/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , beta-Defensinas/genética
5.
Medicine (Baltimore) ; 98(32): e16451, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393349

RESUMO

Early diagnose of bladder cancer could lead to good prognosis and high 5-year-survival rate. Among bladder cancer, about 75% patients with were nonmuscle-invasive bladder cancer (NMIBC). Patients were painful and easily get infected during bladder cancer diagnosis, which mainly depends on invasive cystoscopy and low-sensitivity urine exfoliation cytology. Meanwhile, relapse after surgery was also becoming the major problem for patients. Exploring noninvasive, high-sensitivity, and painless method is very important and meaningful for NMIBC treatment.Firstly, we found potential related gene mutation sites for NMIBC by searching COSMIC database and related study. Urinary sediment cells of patients both in normal group (patients with benign) and NMIMC group were collected before and after operation for potential gene mutation site detecting. Meanwhile, the urinary sediment cells of relapse patients and good prognosis people in NMIBC group after surgery were also collected for further Gene mutation detection and NMIBC relapse after surgery prediction.Fourteen genes (152 mutation sites) were selected between 95 NMIBC patients and 67 control patients, which were FGFR3, TP53, PIK3CA, and others. Compared with control group, mutation ratio of above 14 genes was higher in NMIBC group. NMIBC diagnose model was established by 5 times cross-validation and had a good effects, which included the all mutation site in FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D. On the contrary, the relapse rate was 30.5% among 95 patients for about 1.5-year follow-up time. Compared with control group, smoking rate and tumor grade were higher in relapse group. Meanwhile, mutation rate of FGFR3, TP53, PIK3CA, ERBB3, and TSC1 in relapse group were higher than that in normal group. According to the mutation sites of FGFR3, TP53, PIK3CA, and ERBB3 and the combination of urinary sediment cells genetic mutation and relapse status, a predicted model for NMIBC relapse was also established, which had 90% accuracy.The diagnosed NMIBC model (based on FGFR3, TP53, PIK3CA, ARID1A, STAG2, and KTM2D gene mutation) and predicted relapse model (based on FGFR3, TP53, PIK3CA, and ERBB3 gene mutation) possess high accuracy and would be applied in early diagnose and early predicting relapse of patients.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteína Supressora de Tumor p53/genética , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia , Adulto , Idoso , Biomarcadores Tumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia
6.
Nat Commun ; 10(1): 2977, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278255

RESUMO

Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immune microenvironment; 4) Sporadic UTUC is characterized by a lower total mutational burden than urothelial carcinoma of the bladder. Our findings lay the foundation for a deeper understanding of UTUC biology and provide a rationale for the development of UTUC-specific treatment strategies.


Assuntos
Carcinoma de Células de Transição/patologia , Neoplasias Renais/patologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/metabolismo , Linfócitos T/imunologia , Neoplasias Ureterais/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/imunologia , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Análise de Sequência de RNA , Transdução de Sinais/genética , Microambiente Tumoral/imunologia , Neoplasias Ureterais/genética , Neoplasias Ureterais/imunologia , Urotélio/patologia , Sequenciamento Completo do Exoma
7.
Ann Hematol ; 98(10): 2463-2465, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31240468
8.
APMIS ; 127(8): 545-553, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31231851

RESUMO

microRNA alterations are involved in bladder cancer tumorigenesis. The aim of the current study was to evaluate the potential role of miR-100 and miR-138 as prognostic biomarkers in Ta/T1 non-muscle-invasive bladder cancer (NMIBC). We assessed a quantitative RT-PCR analysis of miR-100 and miR-138 in 50 bladder tumor samples (stage Ta/T1) and four healthy adjacent tissues. Western blot analysis was used to measure protein expression of FGFR3 and cyclin D3 in order to know whether these targets can be regulated by miR-100 and miR-138, respectively. The statistical analysis included non-parametric tests (Mann-Whitney U and Kruskal-Wallis) and univariate survival analysis by Kaplan-Meier method and the log-rank test. Low expression of miR-138 characterized recurrent tumors (p = 0.043), and higher expression levels were associated with longer recurrence-free survival (p = 0.012). However, low miR-100 expression correlated with longer progression-free survival (marginal significance; p = 0.053) and cancer-specific overall survival (p = 0.006). Additionally, higher levels of miR-100 were associated with negative FGFR3 protein expression (p = 0.032) and higher levels of miR-138 were associated with positive cyclin D3 protein expression (p = 0.037). Our results support miR-138 and miR-100 as prognostic biomarkers in patients with NMIBC.


Assuntos
MicroRNAs/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida , Neoplasias da Bexiga Urinária/patologia
9.
Fish Shellfish Immunol ; 92: 224-229, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31200068

RESUMO

Fibroblast growth factor receptor (FGFR) 3 is one of the four distinct membrane-spanning tyrosine kinases required for proper skeletal development. In fish, the role of FGFR3 is still unclear. In this article, we reveal that zebrafish FGFR3 is a negative regulator of interferon (IFN) production in the innate immune response by suppressing the activity of TANK-binding kinase 1 (TBK1) in the process of virus infection. qPCR experiments demonstrate that the transcriptional level of cellular FGFR3 was upregulated by infection with spring viremia of carp virus (SVCV), indicating that FGFR3 might be involved in the process of host cell response to viral infection. Then, overexpression of FGFR3 significantly impeded the IFN promoter activity induced by a stimulator. In addition, the capabilities of a retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) system to activate IFN promoter were decreased during the overexpression of FGFR3. Subsequently, FGFR3 decreased the phosphorylation of interferon regulatory factor 3 (IRF3) and mediator of IRF3 activation (MITA) by TBK1. These findings suggest that zebrafish FGFR3 is a negative regulator of IFN by attenuating the kinase activity of TBK1, leading to the suppression of IFN expression.


Assuntos
Doenças dos Peixes/imunologia , Imunidade Inata/genética , Interferons/genética , Proteínas Serina-Treonina Quinases/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/imunologia , Animais , Interferons/metabolismo , Proteínas Serina-Treonina Quinases/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/imunologia , Rhabdoviridae/fisiologia , Infecções por Rhabdoviridae/imunologia , Infecções por Rhabdoviridae/veterinária , Transdução de Sinais/imunologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/imunologia , Proteínas de Peixe-Zebra/fisiologia
10.
Indian J Dent Res ; 30(2): 185-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31169147

RESUMO

Context: Understanding the role of fibroblast growth factor receptor (FGFR) in the regulation of bone development and disease will ultimately lead to better prevention and treatment of related bone deformities and disorders. Aims: To evaluate the role of gene FGFR3 in individuals with retrognathic maxilla by polymerase chain reaction (PCR) technique at molecular level and evaluate the significance of the same. Settings and Design: Hospital based fundamental research involving individuals having maxillary retrognathism. Methodology: A total of 62 individuals (30M and32F) who were willing to take part in the study were selected from cephalometric measurements of N I A and the length PNS to ANS. The institution based basic genetic research study involved collection of fresh blood samples, DNA extraction, PCR analysis, and amplification using the specifically designed forward and reverse primers for targeting the commonly occurring mutations in FGFR3 gene. Further the products were sequenced to evaluate the presence of any novel mutations. Results: The targeted single-nucleotide polymorphisms, at position 1138 in exon 10 of the FGFR3 gene were not identified in the analyzed blood samples. The detailed sequencing of full gene revealed the presence of 2 novel mutations, Exon 3: A213G and Exon 3: A223A/G in one individual. Conclusions: The present study indicated 2 novel mutations in gene FGFR3 in individual with maxillary retrognathism. The genetic-environmental interactions might have played a significant role in the expression of retrognathic maxilla.


Assuntos
Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Retrognatismo/genética , Humanos , Mutação , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Retrognatismo/epidemiologia
11.
World Neurosurg ; 128: 127-130, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31078809

RESUMO

BACKGROUND: Papillary glioneuronal tumors (PGNTs) are rare World Health Organization grade I neoplasms that are characterized by a benign course and excellent response to surgical resection. A few reports exist of tumors with more aggressive clinical and histologic features. In this report we detail the case of an unusually aggressive PGNT in a 67-year-old woman. CASE DESCRIPTION: The patient had a 3-year history of seizures and was diagnosed with a frontoparietal mass on imaging. She underwent subtotal resection with a histologic diagnosis of PGNT. Less than a year after surgery, the patient experienced recurrence of disease and underwent reresection and adjuvant radiation treatment. The patient's disease continued to progress despite radiation treatment, so adjuvant temozolomide was initiated. Molecular testing was performed and revealed a TERT promotor mutation, an FGFR3-TACC3 oncogenic fusion, and a copy number loss in CDKN2A/CDKN2B. CONCLUSIONS: PGNTs, while typically benign, can rarely recur after surgery. Molecular testing should be performed on all PGNTs to help possibly identify more aggressive tumors and potentially reveal novel treatment options.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Recidiva Local de Neoplasia/patologia , Córtex Somatossensorial/patologia , Idoso , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Proteínas Inibidoras de Quinase Dependente de Ciclina/genética , Variações do Número de Cópias de DNA , Feminino , Glioma/diagnóstico por imagem , Glioma/genética , Glioma/terapia , Humanos , Imagem por Ressonância Magnética , Proteínas Associadas aos Microtúbulos/genética , Mutação , Recidiva Local de Neoplasia/diagnóstico por imagem , Recidiva Local de Neoplasia/terapia , Procedimentos Neurocirúrgicos , Fusão Oncogênica/genética , Regiões Promotoras Genéticas/genética , Radioterapia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Córtex Somatossensorial/diagnóstico por imagem , Córtex Somatossensorial/cirurgia , Telomerase/genética , Tomografia Computadorizada por Raios X
12.
Investig Clin Urol ; 60(3): 148-155, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31098421

RESUMO

Purpose: Multilocular cystic renal neoplasm of low malignant potential (MCRNLMP) and clear cell renal cell carcinoma with cystic change (MCRCC) have different prognoses despite similar histologic characteristics. The aim of this study was to identify differentially mutated genes in resected tumor specimens from patients diagnosed with MCRNLMP and MCRCC using a kidney cancer gene panel. Materials and Methods: Between 2009 and 2016, 13 MCRNLMP and 17 MCRCC cases were selected. Tumor tissues from 5 MCRNLMP and 16 MCRCC cases were subjected to gene sequencing to detect mutations among 88 genes selected from a kidney cancer gene panel after quality control. Fisher's exact test was used to compare gene mutation profiles between the two diseases. Genes were considered to be positive for mutation according to the presence of an in-frame/frameshift deletion or insertion, missense/nonsense mutation, or multi-hit mutation. Results: During a median follow-up period of 66.2 months, there was only one case of MCRCC recurrence among all 30 patients. Target gene sequencing showed that 35 genes tended to be more frequently positive in either disease group, with six genes showing a significantly different frequency of mutation between the groups: GIGYF2 (odds ratio [OR], 5.735), FGFR3 (OR, 6.787), SETD2 (OR, 4.588), BCR (OR, 6.266), KMT2C (OR, 8.167), and TSC2 (OR, 4.474). Conclusions: Six candidate genes showed significantly different mutation patterns between MCRNLMP and MCRCC, providing insight into their pathogenic mechanisms and differential prognoses.


Assuntos
Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/genética , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/patologia , Proteínas de Transporte/genética , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Feminino , Histona-Lisina N-Metiltransferase/genética , Humanos , Doenças Renais Císticas/patologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcr/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Estudos Retrospectivos , Proteína 2 do Complexo Esclerose Tuberosa/genética
13.
Pediatr Dermatol ; 36(4): 554-555, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30983034

RESUMO

We present a 4-year-old developmentally appropriate boy with short stature and widespread expanding epidermal nevus with features of acanthosis nigricans. He was found to have a mosaic mutation in FGFR3, the R248C variant. Despite several therapies, he continued to have growth, fissuring, and bleeding of the affected skin. Ultimately, topical sirolimus was attempted and found to improve thickness and overall symptoms.


Assuntos
Acantose Nigricans/patologia , Nevo/tratamento farmacológico , Nevo/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Sirolimo/uso terapêutico , Acantose Nigricans/genética , Administração Tópica , Pré-Escolar , Diagnóstico Diferencial , Regulação da Expressão Gênica , Humanos , Masculino , Mutação , Nevo/patologia , Medição de Risco , Resultado do Tratamento
14.
World J Urol ; 37(10): 2001-2007, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31028457

RESUMO

PURPOSE: To determine the association between mutations in CDKN2A and FGFR3 genes and the diagnosis of bladder carcinoma (BCa). METHODS: A systematic search strategy was carried out through MEDLINE, EMBASE, LILACS, CENTRAL and unpublished literature. We included RCTs, cohort, case-control and cross-sectional studies that involved patients > 18-year-old assessing the association between CDKN2A and FGFR3 mutated genes and BCa. The primary outcome was bladder cancer defined by histology of the sample. We assessed the risk of bias with QUADAS2 and performed a meta-analysis with Review Manager v5.3. RESULTS: We found 97 records with the search strategies. After duplicates were removed, six studies were included in meta-analysis. Regarding the association between mutated FGFR3 and bladder cancer, we found an OR 31 95% CI (15-64). However, there was no association for CDKN2A and BCa. CONCLUSION: There is a strong association between FGFR3 mutated gene and the diagnosis of bladder cancer, which has not been observed with CDKN2A. Such a result supports FGFR3 mutated gene as a promissory bladder cancer screening and monitoring biomarker.


Assuntos
Genes p16/fisiologia , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Neoplasias da Bexiga Urinária/diagnóstico , Neoplasias da Bexiga Urinária/genética , Humanos
15.
J Exp Clin Cancer Res ; 38(1): 169, 2019 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-30999937

RESUMO

BACKGROUND: FGFR3 plays an important role in the development of bladder cancer (BCa). Hsa_circ_0068871 is a circRNA generated from several exons of FGFR3. However, the potential functional role of hsa_circ_0068871 in BCa remains largely unknown. Here we aim to evaluate the role of hsa_circ_0068871 in BCa. METHODS: We selected miR-181a-5p as the potential target miRNA of hsa_circ_0068871. The expression levels of hsa_circ_0068871 and miR-181a-5p were examined in BCa tissues and paired adjacent normal tissues by quantitative real-time PCR. To characterize the function of hsa_circ_0068871, BCa cell lines were stably infected with lentivirus targeting hsa_circ_0068871, followed by examinations of cell proliferation, migration and apoptosis. In addition, xenografts experiment in nude mice were performed to evaluate the effect of hsa_circ_0068871 in BCa. Biotinylated RNA probe pull-down assay, fluorescence in situ hybridization and luciferase reporter assay were conducted to confirm the relationship between hsa_circ_0068871, miR-181a-5p and FGFR3. RESULTS: Hsa_circ_0068871 is over-expressed in BCa tissues and cell lines, whereas miR-181a-5p expression is repressed. Depletion of has_circ_0068871 or upregulation of miR-181a-5p inhibited the proliferation and migration of BCa cells in vitro and in vivo. Mechanistically, hsa_circ_0068871 upregulated FGFR3 expression and activated STAT3 by targeting miR-181a-5p to promote BCa progression. CONCLUSIONS: Hsa_circ_0068871 regulates the miR-181a-5p/FGFR3 axis and activates STAT3 to promote BCa progression, and it may serve as a potential biomarker.


Assuntos
MicroRNAs/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Fator de Transcrição STAT3/genética , Neoplasias da Bexiga Urinária/genética , Animais , Apoptose/genética , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Lentivirus/genética , Camundongos , RNA/genética , Neoplasias da Bexiga Urinária/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Int J Oncol ; 54(6): 2106-2116, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942430

RESUMO

Benzyl isothiocyanate (BITC) is known for its pharmacological properties against malignant neoplasm, including bladder cancer (BC). The current study investigated microRNAs (miRNA or miR) expression profiles with an emphasis on the role of miR­99a­5p in BITC­treated BC cells. A quantitative polymerase chain reaction (qPCR) microarray containing 79 aberrantly expressed miRNAs in BC was used to detect miRNA expression in BITC­treated cells. Several dysregulated miRNAs were identified and further confirmed using miRNA stem­loop reverse transcription (RT)­qPCR in 5637 cells. Insulin­like growth factor 1 receptor (IGF1R), fibroblast growth factor receptor 3 (FGFR3) and mammalian target of rapamycin (mTOR) expression were determined by RT­qPCR and western blotting. Cell viability was evaluated using WST­1 reagent and apoptosis was monitored by determining the levels of cleaved­poly ADP­ribose polymerase and cleaved­caspase­3. BITC treatment significantly upregulated miR­99a­5p levels in a dose­dependent manner. miR­99a­5p overexpression decreased IGF1R, mTOR and FGFR3 expression, predicted targets of miR­99a­5p. In addition, antisense miR­99a­5p sequences inhibited BITC­induced miR­99a­5p overexpression, resulting in the restoration of protein expression and decreased cell viability. The current study identified multiple miRNAs responsive to BITC treatment, including miR­99a­5p. In addition, the induction of miR­99a­5p decreased IGF1R, mTOR and FGFR3 expression in BITC­treated BC cells. The current study provided novel insight into the antitumor mechanism by which BITC restores miR­99a­5p expression and decreases cancer cell survival.


Assuntos
Antineoplásicos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Isotiocianatos/farmacologia , MicroRNAs/metabolismo , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Humanos , Isotiocianatos/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptores de Somatomedina/genética , Serina-Treonina Quinases TOR/genética , Regulação para Cima/efeitos dos fármacos , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
17.
Cancer Sci ; 110(5): 1771-1779, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30887605

RESUMO

Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non-invasive test for detecting UTUC, but its sensitivity is low. A novel non-invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell-free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ≤pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger-scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non-invasive diagnostic marker and reliable factor for tumor staging.


Assuntos
Carcinoma de Células de Transição/diagnóstico , Ácidos Nucleicos Livres/urina , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Telomerase/genética , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Carcinoma de Células de Transição/genética , Carcinoma de Células de Transição/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Regiões Promotoras Genéticas , Sensibilidade e Especificidade , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/urina
18.
Pediatr Dermatol ; 36(2): 242-246, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30762251

RESUMO

Early development of extensive acanthosis nigricans (AN) is a key feature in some patients who have hypochondroplasia (HCH) in association with FGFR3 mutations. We here report regarding five new patients with HCH who exhibited AN, and we compare their characteristics to the eight patients previously described in the literature. In these patients, the AN lesions began in childhood, and they were extensive. These lesions were located on the torso, the abdomen, and the face, in addition to the typical skin fold sites. Other skin lesions were frequently reported: café-au-lait macules, melanocytic nevi, lentigines, and seborrheic keratosis. The Lys650Thr mutation was the predominant reported mutation of FGFR3.


Assuntos
Acantose Nigricans/genética , Osso e Ossos/anormalidades , Nanismo/genética , Deformidades Congênitas dos Membros/genética , Lordose/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acantose Nigricans/complicações , Adulto , Criança , Nanismo/complicações , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Deformidades Congênitas dos Membros/complicações , Lordose/complicações , Masculino , Mutação , Fenótipo , Pele/patologia , Adulto Jovem
20.
BMC Med Genet ; 20(1): 8, 2019 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-30635042

RESUMO

BACKGROUND: Acanthosis nigricans (AN) is a clinical manifestation featured by velvety brown plaques in skin folds that occurs in some hereditary and syndromic disorders. Fibroblast growth factor receptor 3 (FGFR3) mutations have been identified as one of the genetic causes of inherited AN. CASE PRESENTATION: A 17-year-old Chinese female had presented generalized acanthosis nigricans since she was 4 years old. She yielded no family history of short stature or AN. Apart from a short stature, no skeletal defects, neurological defects or other abnormalities were found. To identify the aetiology of the clinically diagnosed AN, we screened the proband for genetic mutations using whole exome sequencing. A heterozygous mutation (c.1949A > C, p.Lys650Thr) in FGFR3 was found in the proband. To date, 26 cases of AN harbouring this specific gene mutation have been reported in the literature, and only one child carried a de novo mutation instead of inheriting the specific mutation from their parents. The present case is the first-reported Chinese patient with isolated AN with a de novo K650 T mutation in FGFR3. CONCLUSIONS: We reported a new case of AN caused by a heterozygous mutation (c.1949A > C, p.K650 T) in FGFR3, and review the past reports of AN with the same gene mutation. Sequencing of the FGFR3 gene is a feasible approach to identify the aetiology of AN, especially for early onset extensive AN.


Assuntos
Acantose Nigricans/genética , Predisposição Genética para Doença , Mutação , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Acantose Nigricans/diagnóstico , Acantose Nigricans/fisiopatologia , Adolescente , Grupo com Ancestrais do Continente Asiático , Análise Mutacional de DNA , Nanismo/genética , Éxons , Feminino , Heterozigoto , Humanos , Linhagem , Sequenciamento Completo do Exoma
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