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1.
Breast Cancer Res Treat ; 195(1): 17-31, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35793004

RESUMO

PURPOSE: Platelet-derived growth factor B (PDGFB) is known to play essential roles in angiogenesis and lymphangiogenesis during development, and tumor growth and vessel stabilization in experimental models. However, whether these findings could be translated to breast cancer patients remains unclear. We hypothesized that PDGFB gene expression is associated with angiogenesis, cell proliferation, and clinical outcomes in breast cancer patients. METHODS: A total of 7635 primary breast cancer patients with full transcriptome and clinical data available from 13 independent cohorts were analyzed using in silico approach. The median value was used to divide each cohort into high and low PDGFB expression groups. RESULTS: High PDGFB gene expression was associated with increased expression of angiogenesis-related genes, higher amount of vascular cell infiltrations, and with enrichment of angiogenesis gene set, lymphangiogenesis-related gene expressions, lymphangiogenesis-related cell infiltrations, and enrichmentof lymphangiogenesis gene set in GSE96058 and validated by TCGA cohorts; however, not with lymphatic metastasis. PDGFB expression was neither associated with cell proliferation as assessed by Ki67 expression nor with Nottingham histological grade, or response to neoadjuvant chemotherapy. We found that PDGFB was most extensively expressed by endothelial and perivascular-like cells in the tumor microenvironment, and minimally by cancer cells consistently in two single-cell sequence cohorts. High PDGFB expression enriched TGFß, epithelial-mesenchymal transition, hypoxia, and cancer stem cell-associated pathways. However, no association with distant metastasis was observed. Disease-specific and disease-free survival were worse in the high PDGFB expression group consistently in TCGA and METABRIC cohorts. CONCLUSION: PDGFB is predominantly expressed in endothelial cells and is associated with angiogenesis and lymphangiogenesis, but not with cellular proliferation or metastasis in breast cancer.


Assuntos
Neoplasias da Mama , Linfangiogênese , Neoplasias da Mama/patologia , Células Endoteliais/metabolismo , Feminino , Genes sis , Humanos , Linfangiogênese/genética , Neovascularização Patológica/genética , Proteínas Proto-Oncogênicas c-sis/genética , Microambiente Tumoral
2.
BMC Musculoskelet Disord ; 22(1): 710, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34407802

RESUMO

BACKGROUND: There is variability in individual response to platelet-rich plasma (PRP) therapy in tennis elbow treatment. Genetic variation, especially within genes encoding growth factors may influence the observed inter-individual differences. The purpose of this study was to identify polymorphic variants of the platelet-derived growth factor beta polypeptide gene (PDGFB) that determine an improved individual response to PRP therapy in tennis elbow patients. METHODS: This prospective cohort study was designed in accordance with STROBE and MIBO guidelines. A cohort of 107 patients (132 elbows, 25 bilateral) was studied, including 65 females (77 elbows) and 42 males (55 elbows), aged 24-64 years (median 46.00 ± 5.50), with lateral elbow tendinopathy treated with autologous PRP injection. The effectiveness of PRP therapy was recorded in all subjects at 2, 4, 8, 12, 24 and 52 weeks after PRP injection using the Visual Analog Scale (VAS), quick version of Disabilities of the Arm, Shoulder and Hand score (QDASH) and Patient-Rated Tennis Elbow Evaluation (PRTEE). In order to determine the PDGFB variants with the best response to PRP therapy, patient reported outcome measures were compared between individual genotypes within studied polymorphic variants (rs2285099, rs2285097, rs2247128, rs5757572, rs1800817 and rs7289325). The influence of single nucleotide polymorphisms on blood and PRP parameters, including the concentration of PDGF-AB and PDGF-BB proteins was also analyzed. RESULTS: Our analysis identified genetic variants of the PDGFB gene that lead to a better response to PRP therapy. The TT (rs2285099) and CC (rs2285097) homozygotes had higher concentration of platelets in whole blood than carriers of other genotypes (p = 0.018) and showed significantly (p < 0.05) lower values of VAS (weeks 2-12), QDASH and PRTEE (weeks 2-24). The rs2285099 and rs2285097 variants formed strong haplotype block (r2 = 98, D'=100). The AA homozygotes (rs2247128) had significantly lower values of VAS (weeks 4-52), QDASH and PRTEE (weeks 8, 12). CONCLUSIONS: PDGFB gene's polymorphisms increase the effectiveness of PRP therapy in tennis elbow treatment. Genotyping two polymorphisms of the PDGFB gene, namely rs2285099 (or rs2285097) and rs2247128 may be a helpful diagnostic tool while assessing patients for PRP therapy and modifying the therapy to improve its effectiveness.


Assuntos
Genes sis , Plasma Rico em Plaquetas , Tendinopatia , Cotovelo de Tenista , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Cotovelo de Tenista/diagnóstico , Cotovelo de Tenista/genética , Cotovelo de Tenista/terapia
3.
Mov Disord ; 36(11): 2468-2480, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34432325

RESUMO

This systematic MDSGene review covers individuals with confirmed genetic forms of primary familial brain calcification (PFBC) available in the literature. Data on 516 (47% men) individuals, carrying heterozygous variants in SLC20A2 (solute carrier family 20 member 2, 61%), PDGFB (platelet-derived growth factor subunit B, 12%), XPR1 (xenotropic and polytropic retrovirus receptor, 16%), or PDGFRB (platelet-derived growth factor receptor beta, 5%) or biallelic variants in MYORG (myogenesis-regulating glycosidase, 13%) or JAM2 (junctional adhesion molecule 2, 2%), were extracted from 93 articles. Nearly one-third of the mutation carriers were clinically unaffected. Carriers of PDGFRB variants were more likely to be clinically unaffected (~54%), and the penetrance of SLC20A2 and XPR1 variants (<70%) was lower in comparison to the remaining three genes (>85%). Among the 349 clinically affected patients, 27% showed only motor and 31% only nonmotor symptoms/signs, whereas the remaining 42% had a combination thereof. While parkinsonism and speech disturbance were the most frequently reported motor manifestations, cognitive deficits, headache, and depression were the major nonmotor symptoms/signs. The basal ganglia were always calcified, and the cerebellum, thalamus, and white matter contained calcifications in 58%, 53%, and 43%, respectively, of individuals. In autosomal-dominant PFBC, mutation severity influenced the number of calcified brain areas, which in turn correlated with the clinical status, whereby the risk of developing symptoms/signs more than doubled for each additional region with calcifications. Our systematic analysis provides the most comprehensive insight into genetic, clinical, and neuroimaging features of known PFBC forms, to date. In addition, it puts forth the penetrance estimates and newly discovered genotype-phenotype relations that will improve counseling of individuals with mutations in PFBC genes. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Encefalopatias , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encefalopatias/genética , Genes sis , Heterozigoto , Humanos , Mutação , Fenótipo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética
4.
Genes Chromosomes Cancer ; 60(3): 147-159, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33099837

RESUMO

The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.


Assuntos
Receptor trkA/metabolismo , Sarcoma/metabolismo , Neoplasias Uterinas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cadeia alfa 1 do Colágeno Tipo I/genética , Feminino , Fusão Gênica/genética , Rearranjo Gênico , Genes sis , Humanos , Imuno-Histoquímica , Recidiva Local de Neoplasia/enzimologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Receptor trkA/genética , Sarcoma/enzimologia , Sarcoma/genética , Sarcoma do Estroma Endometrial/enzimologia , Sarcoma do Estroma Endometrial/genética , Sarcoma do Estroma Endometrial/metabolismo , Neoplasias de Tecidos Moles/genética
5.
Hum Mutat ; 40(4): 392-403, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30609140

RESUMO

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder with four causative genes (SLC20A2, PDGFRB, PDGFB, and XPR1) that have been identified. Here, we aim to describe the mutational spectrum of four causative genes in a series of 226 unrelated Chinese PFBC patients. Mutations in four causative genes were detected in 16.8% (38/226) of PFBC patients. SLC20A2 mutations accounted for 14.2% (32/226) of all patients. Mutations in the other three genes were relatively rare, accounting for 0.9% (2/226) of all patients, respectively. Clinically, 44.8% of genetically confirmed patients (probands and relatives) were considered symptomatic. The most frequent symptoms were chronic headache, followed by movement disorders and vertigo. Moreover, the total calcification score was significantly higher in the symptomatic group compared to the asymptomatic group. Functionally, we observed impaired phosphate transport induced by seven novel missense mutations in SLC20A2 and two novel mutations in XPR1. The mutation p.D164Y in XPR1 might result in low protein expression through an enhanced proteasome pathway. In conclusion, our study further confirms that mutations in SLC20A2 are the major cause of PFBC and provides additional evidence for the crucial roles of phosphate transport impairment in the pathogenies of PFBC.


Assuntos
Encefalopatias/genética , Calcinose/genética , Predisposição Genética para Doença , Mutação , Doenças Neurodegenerativas/genética , Adulto , Idoso , Alelos , Transporte Biológico , Biomarcadores , Encefalopatias/diagnóstico , Encefalopatias/metabolismo , Calcinose/diagnóstico , Calcinose/metabolismo , Linhagem Celular Tumoral , China , Feminino , Genes sis , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/metabolismo , Neuroimagem , Fenótipo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Receptores Acoplados a Proteínas G/genética , Receptores Virais/genética , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Tomografia Computadorizada por Raios X , Receptor do Retrovírus Politrópico e Xenotrópico
6.
Medicine (Baltimore) ; 97(42): e12918, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30335026

RESUMO

Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurological and psychiatric symptoms. In families displaying an autosomal dominant inheritance pattern, three causative genes have been identified: SLC20A2, PDGFRB, and very recently, PDGFB. While in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrences are rare. We report a case of a 61-year-old woman who presented with depressive and dystonic symptoms revealing IBGC. Her 41-year-old daughter was healthy. In the proband, we identified 4 mutations in PDGFB, and 1 exonic mutation in SLC20A2, all of which were absent in the daughter. These mutations may result in a loss-of-function of PDGF-B or SLC20A2, which has been shown to cause IBGC in humans and disrupts the blood-brain barrier in mice resulting in brain calcification. Herein, we present the occurrence of a sporadic patient of IBGC and its causative mutations.


Assuntos
Doenças dos Gânglios da Base/genética , Calcinose/genética , Adulto , Animais , Éxons/genética , Feminino , Genes sis/genética , Humanos , Camundongos , Pessoa de Meia-Idade , Mutação/genética , Núcleo Familiar , Linhagem , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , República da Coreia , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/genética , Sequenciamento do Exoma
8.
Oncotarget ; 6(11): 9517-30, 2015 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-25940705

RESUMO

Neuroblastoma is a common childhood malignant tumor originated from the neural crest-derived sympathetic nervous system. A crucial event in the pathogenesis of neuroblastoma is to promote proliferation of neuroblasts, which is closely related to poor survival. However, mechanisms for regulation of cell proliferation and tumorigenicity in neuroblastoma are not well understood. Here, we report that overexpression of TAZ in neuroblastoma BE(2)-C cells causes increases in cell proliferation, self renewal and colony formation, which was restored back to its original levels by knockdown of TAZ in TAZ-overexpression cells. Inhibition of endogenous TAZ attenuated cell proliferation, colony formation and tumor development in neuroblastoma SK-N-AS cell, which could be rescued by re-introduction of TAZ into TAZ-knockdown cells. In addition, we found that overexpressing TAZ-mediated induction of CTGF and PDGF-ß expression, cell proliferation and colony formation were inhibited by knocking down CTGF and PDGF-ß with siRNA in TAZ-overexpressing cell. Overall, our findings suggested that TAZ plays an essential role in regulating cell proliferation and tumorigenesis in neuroblastoma cells. Thus, TAZ seems to be a novel and promising target for the treatment of neuroblastoma.


Assuntos
Regulação Neoplásica da Expressão Gênica , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Proteínas de Neoplasias/fisiologia , Neuroblastoma/patologia , Animais , Adesão Celular , Divisão Celular , Linhagem Celular Tumoral , Fator de Crescimento do Tecido Conjuntivo/antagonistas & inibidores , Fator de Crescimento do Tecido Conjuntivo/biossíntese , Fator de Crescimento do Tecido Conjuntivo/genética , Genes sis , Xenoenxertos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Terapia de Alvo Molecular , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Prognóstico , Proteínas Proto-Oncogênicas c-sis/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-sis/biossíntese , Interferência de RNA , RNA Interferente Pequeno/genética , Proteínas Recombinantes de Fusão/metabolismo , Taxa de Sobrevida , Transativadores , Fatores de Transcrição , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Transfecção , Ensaio Tumoral de Célula-Tronco
10.
J Biol Chem ; 289(34): 23712-22, 2014 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-24973215

RESUMO

The presence of the blood-brain barrier (BBB) is critical for cholesterol metabolism in the brain, preventing uptake of lipoprotein-bound cholesterol from the circulation. The metabolic consequences of a leaking BBB for cholesterol metabolism have not been studied previously. Here we used a pericyte-deficient mouse model, Pdgfb(ret/ret), shown to have increased permeability of the BBB to a range of low-molecular mass and high-molecular mass tracers. There was a significant accumulation of plant sterols in the brains of the Pdgfb(ret/ret) mice. By dietary treatment with 0.3% deuterium-labeled cholesterol, we could demonstrate a significant flux of cholesterol from the circulation into the brains of the mutant mice roughly corresponding to about half of the measured turnover of cholesterol in the brain. We expected the cholesterol flux into the brain to cause a down-regulation of cholesterol synthesis. Instead, cholesterol synthesis was increased by about 60%. The levels of 24(S)-hydroxycholesterol (24S-OHC) were significantly reduced in the brains of the pericyte-deficient mice but increased in the circulation. After treatment with 1% cholesterol in diet, the difference in cholesterol synthesis between mutants and controls disappeared. The findings are consistent with increased leakage of 24S-OHC from the brain into the circulation in the pericyte-deficient mice. This oxysterol is an efficient suppressor of cholesterol synthesis, and the results are consistent with a regulatory role of 24S-OHC in the brain. To our knowledge, this is the first demonstration that a defective BBB may lead to increased flux of a lipophilic compound out from the brain. The relevance of the findings for the human situation is discussed.


Assuntos
Barreira Hematoencefálica , Encéfalo/metabolismo , Colesterol/metabolismo , Homeostase , Animais , Sequência de Bases , Colesterol/biossíntese , Primers do DNA , Genes sis , Homeostase/genética , Camundongos , Camundongos Transgênicos , Plantas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Esteróis/metabolismo
11.
Int J Radiat Oncol Biol Phys ; 89(3): 599-606, 2014 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-24929166

RESUMO

PURPOSE: The late side effects of kidney irradiation include vascular damage and fibrosis, which are promoted by an irradiation-induced inflammatory response. We therefore treated kidney-irradiated mice with the anti-inflammatory and angiogenesis-modulating drug thalidomide in an attempt to prevent the development of late normal tissue damage and radiation nephropathy in the mouse kidney. METHODS AND MATERIALS: Kidneys of C57Bl/6 mice were irradiated with a single dose of 14 Gy. Starting from week 16 after irradiation, the mice were fed with thalidomide-containing chow (100 mg/kg body weight/day). Gene expression and kidney histology were analyzed at 40 weeks and blood samples at 10, 20, 30, and 40 weeks after irradiation. RESULTS: Thalidomide improved the vascular structure and vessel perfusion after irradiation, associated with a normalization of pericyte coverage. The drug also reduced infiltration of inflammatory cells but could not suppress the development of fibrosis. Irradiation-induced changes in hematocrit and blood urea nitrogen levels were not rescued by thalidomide. Moreover, thalidomide worsened tubular damage after irradiation and also negatively affected basal tubular function. CONCLUSIONS: Thalidomide improved the inflammatory and vascular side effects of kidney irradiation but could not reverse tubular toxicity, which probably prevented preservation of kidney function.


Assuntos
Moduladores da Angiogênese/farmacologia , Anti-Inflamatórios/farmacologia , Túbulos Renais/efeitos dos fármacos , Rim/efeitos da radiação , Lesões Experimentais por Radiação/prevenção & controle , Talidomida/farmacologia , Moduladores da Angiogênese/efeitos adversos , Animais , Anti-Inflamatórios/efeitos adversos , Feminino , Fibrose , Genes sis/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos da radiação , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Rim/patologia , Túbulos Renais/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Nefrite/patologia , Nefrite/prevenção & controle , Talidomida/efeitos adversos
12.
Breast Cancer Res Treat ; 140(3): 587-601, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23912956

RESUMO

Growth factors (GF) stimulate cell proliferation through binding to cell membrane receptors and are thought to be involved in cancer risk and survival. We examined how genetic variation in epidermal growth factor (EGF), neuregulin 2 (NRG2), ERBB2 (HER2/neu), fibroblast growth factors 1 and 2 (FGF1 and FGF2) and its receptor 2 (FGFR2), and platelet-derived growth factor B (PDGFB) independently and collectively influence breast cancer risk and survival. We analyzed data from the Breast Cancer Health Disparities Study which includes Hispanic (2,111 cases, 2,597 controls) and non-Hispanic white (1,481 cases, 1,586 controls) women. Adaptive rank-truncated product (ARTP) analysis was conducted to determine gene significance. Odds ratios (OR) and 95 % confidence intervals were obtained from conditional logistic regression models to estimate breast cancer risk and Cox proportional hazard models were used to estimate hazard ratios (HR) of dying from breast cancer. We assessed Native American (NA) ancestry using 104 ancestry informative markers. We observed few significant associations with breast cancer risk overall or by menopausal status other than for FGFR2 rs2981582. This SNP was significantly associated with ER+/PR+ (OR 1.66, 95 % CI 1.37-2.00) and ER+/PR- (OR 1.54, 95 % CI 1.03-2.31) tumors. Multiple SNPs in FGF1, FGF2, and NRG2 significantly interacted with multiple SNPs in EGFR, ERBB2, FGFR2, and PDGFB, suggesting that breast cancer risk is dependent on the collective effects of genetic variants in other GFs. Both FGF1 and ERBB2 significantly influenced overall survival, especially among women with low levels of NA ancestry (P ARTP = 0.007 and 0.003, respectively). Our findings suggest that genetic variants in growth factors signaling appear to influence breast cancer risk through their combined effects. Genetic variation in ERBB2 and FGF1 appear to be associated with survival after diagnosis with breast cancer.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adulto , Idoso , Estudos de Casos e Controles , Fator de Crescimento Epidérmico/genética , Feminino , Fator 1 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/genética , Genes erbB-2 , Genes sis , Hispânico ou Latino/genética , Humanos , Indígenas Norte-Americanos/genética , Pessoa de Meia-Idade , Fatores de Crescimento Neural/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , População Branca/genética
13.
J Med Invest ; 60(1-2): 106-13, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23614918

RESUMO

Fibroblast growth factors (FGFs) and their receptors (FGFRs) control a wide range of biological functions; however, their involvement in the pathogenesis of dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) is currently unknown. In this study, we first confirmed the histological diagnosis by detecting fusion COL1A1-PDGFB transcripts in DFSP, and examined the expression of all FGFRs (FGFR1-4), some of their ligands (FGF1, 2, 9), and forkhead box N1 (FOXN1) as a downstream target of FGFR3 in DF and DFSP by immunohistochemical analysis. Although we failed to detect the expression of FGF1 and FGF9 as specific ligands for FGFR3 in DF, overexpression of FGFR3 and FOXN1 was observed in the epidermal regions of DF, suggesting that the epidermal regions of DF were similar to seborrhoeic keratosis both in terms of histological features and the activation of FGFR3/FOXN1. In addition, strong expression of FGF2 and FGFR4 was observed in the tumor lesions of DF. Expression patterns of FGFR3/FOXN1 and FGF2/FGFR4 in DF were in contrast with those of DFSP. The activation of FGFR signaling pathways may be not only relevant to the pathogenesis of DF, but also very useful in the differential diagnosis of DF and DFSP.


Assuntos
Dermatofibrossarcoma/etiologia , Histiocitoma Fibroso Benigno/etiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais/fisiologia , Adulto , Idoso , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Dermatofibrossarcoma/metabolismo , Feminino , Fatores de Transcrição Forkhead/análise , Genes sis , Histiocitoma Fibroso Benigno/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Fatores de Crescimento de Fibroblastos/análise
14.
Biochem Biophys Res Commun ; 434(2): 305-10, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23537647

RESUMO

We have reported that the oncoprotein hepatitis B virus X-interacting protein (HBXIP) acts as a novel transcriptional coactivator to promote proliferation and migration of breast cancer cells. Previously, we showed that HBXIP was able to activate nuclear factor-κB (NF-κB) in breast cancer cells. As an oncogene, the platelet-derived growth factor beta polypeptide (PDGFB) plays crucial roles in carcinogenesis. In the present study, we found that both HBXIP and PDGFB were highly expressed in breast cancer cell lines. Interestingly, HBXIP was able to increase transcriptional activity of NF-κB through PDGFB, suggesting that HBXIP is associated with PDGFB in the cells. Moreover, HBXIP was able to upregulate PDGFB at the levels of mRNA, protein and promoter in the cells. Then, we identified that HBXIP stimulated the promoter of PDGFB through activating transcription factor Sp1. In function, HBXIP enhanced the proliferation of breast cancer cells through PDGFB in vitro. Thus, we conclude that HBXIP upregulates PDGFB via activating transcription factor Sp1 to promote proliferation of breast cancer cells.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/patologia , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Genes sis , Fator de Transcrição Sp1/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Neoplasias da Mama/metabolismo , Imunoprecipitação da Cromatina , Clonagem Molecular , Feminino , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Células MCF-7 , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , Plasmídeos/genética , Plasmídeos/metabolismo , Regiões Promotoras Genéticas , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Fator de Transcrição Sp1/genética , Ativação Transcricional , Regulação para Cima
15.
Pathol Res Pract ; 209(1): 30-5, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-23207290

RESUMO

Dermatofibrosarcoma protuberans (DFSP) is a dermal and subcutaneous tumor of intermediate malignancy. The most remarkable cytogenetic feature of DFSP is the chromosomal translocation t(17;22)(q22;q13), causing a fusion of the platelet-derived growth factor beta chain (PDGFB) gene at 22q13, and the collagen type 1 alpha 1 (COL1A1) at 17q22. The aim of the study was to analyze the molecular characteristic of DFSP in conjunction with histopathological and clinical features. We performed fluorescence in situ hybridization (FISH) and multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) to detect chromosomal translocations and fusion gene transcripts in 16 formalin-fixed, paraffin-embedded DFSP samples. In addition, the amplification of PDGFB was also evaluated in the 16 DFSP samples by real-time PCR. FISH analysis revealed that all the 16 samples exhibited COL1A1-PDGFB gene fusion. Eleven out of 11 informative cases (100%) showed fusion transcripts by multiplex RT-PCR analysis. Various exons of the COL1A1 gene were fused with the PDGFB gene. Among them, exon 25 was found to be more frequently involved. Real-time PCR showed that the PDGFB copy number increase in the DFSP samples was higher than in normal skin tissues (p=0.007). Values of FISH fusion signals and PDGFB DNA analysis were variable between samples, but suggested that increased values might be associated with parameters of tumor progression. Our results confirm that analysis of the COL1A1-PDGFB status by FISH and RT-PCR is a useful tool in the confirmation of a DFSP diagnosis. In addition, the analysis of PDGFB copy number status may become a useful diagnostic marker since the gene is a potential target for treatment of DFSP patients.


Assuntos
Colágeno Tipo I/genética , Dermatofibrossarcoma/genética , Genes sis/genética , Proteínas de Fusão Oncogênica/genética , Adulto , Idoso de 80 Anos ou mais , Cadeia alfa 1 do Colágeno Tipo I , Feminino , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
Proc Natl Acad Sci U S A ; 109(9): 3475-80, 2012 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-22345562

RESUMO

Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin ß1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients.


Assuntos
Neoplasias Encefálicas/patologia , Terapia Genética , Vetores Genéticos/uso terapêutico , Glioblastoma/patologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/fisiologia , Integrina beta1/fisiologia , NF-kappa B/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Animais , Astrocitoma/genética , Astrocitoma/metabolismo , Proteínas Aviárias/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Genes Sintéticos , Genes sis , Vetores Genéticos/administração & dosagem , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/toxicidade , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/biossíntese , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/toxicidade , Proteínas de Filamentos Intermediários/genética , Estimativa de Kaplan-Meier , Camundongos , Camundongos Transgênicos , Inibidor de NF-kappaB alfa , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Nestina , Oligodendroglioma/genética , Oligodendroglioma/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/toxicidade , Receptores Virais/genética , Retroviridae , Transdução de Sinais/fisiologia
17.
Glia ; 58(9): 1050-65, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20468047

RESUMO

Glial progenitors in the white matter and the subventricular zone are the major population of cycling cells in the postnatal central nervous system, and thought to be candidates for glioma-initiating cells. However, less is known about the dividing cell populations in the brainstem than those in the cerebrum, leading to the lag of basic understanding of brainstem gliomas. We herein demonstrate much fewer cycling glial progenitors exist in the brainstem than in the cerebrum. We also show that infecting brainstem glial progenitors with PDGFB-green fluorescent protein (GFP)-expressing retrovirus induced tumors that closely resembled human malignant gliomas. Of note, brainstem tumors grew more slowly than cerebral tumors induced by the same retrovirus, and >80% tumor cells in the brainstem consisted of GFP-positive, infected progenitors while GFP-positive cells in the cerebral tumors were <20%. These indicate that cerebral tumors progressed rapidly by recruiting resident progenitors via paracrine mechanism whereas brainstem tumors grew more slowly by clonal expansion of the infected population. The cerebral and brainstem glial progenitors similarly showed reversible dedifferentiation upon PDGF stimulation in vitro and did not show the intrinsic difference in terms of the responsiveness to PDGF. We therefore suggest that slower, monoclonal progression pattern of the brainstem tumors is at least partly due to the environmental factors including the cell density of the glial progenitors. Together, these findings are the first implications regarding the cell-of-origin and the gliomagenesis in the brainstem.


Assuntos
Neoplasias do Tronco Encefálico/fisiopatologia , Tronco Encefálico/fisiopatologia , Glioma/fisiopatologia , Neuroglia/fisiologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Células-Tronco/fisiologia , Animais , Neoplasias Encefálicas/fisiopatologia , Tronco Encefálico/patologia , Neoplasias do Tronco Encefálico/patologia , Diferenciação Celular , Células Cultivadas , Cerebelo/fisiologia , Criança , Feminino , Genes sis , Vetores Genéticos , Glioma/patologia , Proteínas de Fluorescência Verde/genética , Humanos , Masculino , Fator de Crescimento Derivado de Plaquetas/genética , Ratos , Retroviridae
18.
Histopathology ; 54(7): 860-72, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19635106

RESUMO

AIMS: To analyse the presence of collagen type I alpha 1-platelet-derived growth factor beta (COL1A1-PDGFB) transcripts in 20 cases of dermatofibrosarcoma protuberans (DFSP) and to assess the relationship between COL1A1 breakpoints and clinical and histopathological variables. METHODS AND RESULTS: Multiplex reverse transcriptase-polymerase chain reaction was carried out using frozen tissue. Our series contained 14 men and six women. Histologically, most cases were of conventional type (n = 9), followed by fibrosarcoma (n = 4), Bednar tumour (n = 2), sclerosing (n = 2), myoid (n = 1) and atrophic (n = 1) DFSP, and giant cell fibroblastoma (n = 1). Immunohistochemistry revealed CD34 expression in 90% of cases. COL1A1-PDGFB fusion transcripts were present in 89% of cases (exons 18, 19, 20, 25, 26, 31, 33/34, 39, 40, 46, 47 and 48 of COL1A1 with exon 2 of PDGFB). There was no recurrence of DFSP in any of the 19 patients treated by Mohs surgery. A partial response was obtained in the two patients treated with imatinib. CONCLUSIONS: The COL1A1-PDGFB fusion was present in all histological subtypes of DFSP, but not all cases expressed the fusion transcript. No association was observed between different COL1A1 breakpoints and clinicopathological parameters. Imatinib mesylate can be useful in locally advanced tumours and metastases.


Assuntos
Colágeno Tipo I/genética , Dermatofibrossarcoma/genética , Dermatofibrossarcoma/patologia , Genes sis , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Sequência de Bases , Benzamidas , Cadeia alfa 1 do Colágeno Tipo I , Primers do DNA/genética , Dermatofibrossarcoma/terapia , Feminino , Fusão Gênica , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Cirurgia de Mohs , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Neoplasias Cutâneas/terapia , Adulto Jovem
19.
Nephrol Dial Transplant ; 24(2): 448-57, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18775895

RESUMO

BACKGROUND: Morphological changes associated with long-term peritoneal dialysis (PD) include increased vascular surface area due to angiogenesis, submesothelial fibrosis and epithelial mesenchymal transition. Platelet-derived growth factor (PDGF) has been associated with all of these phenomena, and is a prototypical 'response to injury' growth factor. METHODS: Rats received an intraperitoneal injection of adenoviral vector expressing PDGF-B. At sacrifice, we analysed the structure and function of the peritoneal membrane. Gene expression in the peritoneal tissue was assessed for changes suggestive of epithelial mesenchymal transition. RESULTS: Over-expression of PDGF in the rat peritoneum led to significant angiogenesis, cellular proliferation and submesothelial thickening. Although PDGF induced expression of transforming growth factor beta, there was a lack of activation of this growth factor, and we believe that this explains the lack of significant collagen accumulation observed by a hydroxyproline assay. Despite evidence of angiogenesis and subsequent increased solute transport, we observed only a transient, non-significant impact on ultrafiltration function. This suggests that increased vascular surface area is necessary, but not sufficient, to produce ultrafiltration dysfunction. There was no evidence of epithelial mesenchymal transition observed either in regulation of associated genes such as Snail or E-Cadherin or in the lack of dual-labelled epithelial and mesenchymal cells on immunofluorescence. Mesothelial cells exposed to PDGF-B demonstrated increased collagen gene expression. CONCLUSIONS: PDGF-B induced angiogenesis without fibrosis in the peritoneum. The lack of significant ultrafiltration dysfunction and epithelial mesenchymal transition, as observed in patients on PD, suggests that PDGF-B may play a role, but is not the integral component, in response to peritoneal injury.


Assuntos
Peritônio/patologia , Peritônio/fisiopatologia , Proteínas Proto-Oncogênicas c-sis/fisiologia , Adenoviridae/genética , Animais , Colágeno/genética , Colágeno Tipo I , Epitélio/patologia , Expressão Gênica , Genes sis , Vetores Genéticos , Humanos , Mesoderma/patologia , Neovascularização Patológica , Diálise Peritoneal/efeitos adversos , Peritônio/irrigação sanguínea , Inibidor 1 de Ativador de Plasminogênio/genética , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-sis/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo
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