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1.
Am J Hum Genet ; 102(6): 1018-1030, 2018 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-29754768

RESUMO

Coenzyme A (CoA) is an essential metabolic cofactor used by around 4% of cellular enzymes. Its role is to carry and transfer acetyl and acyl groups to other molecules. Cells can synthesize CoA de novo from vitamin B5 (pantothenate) through five consecutive enzymatic steps. Phosphopantothenoylcysteine synthetase (PPCS) catalyzes the second step of the pathway during which phosphopantothenate reacts with ATP and cysteine to form phosphopantothenoylcysteine. Inborn errors of CoA biosynthesis have been implicated in neurodegeneration with brain iron accumulation (NBIA), a group of rare neurological disorders characterized by accumulation of iron in the basal ganglia and progressive neurodegeneration. Exome sequencing in five individuals from two unrelated families presenting with dilated cardiomyopathy revealed biallelic mutations in PPCS, linking CoA synthesis with a cardiac phenotype. Studies in yeast and fruit flies confirmed the pathogenicity of identified mutations. Biochemical analysis revealed a decrease in CoA levels in fibroblasts of all affected individuals. CoA biosynthesis can occur with pantethine as a source independent from PPCS, suggesting pantethine as targeted treatment for the affected individuals still alive.


Assuntos
Cardiomiopatia Dilatada/enzimologia , Cardiomiopatia Dilatada/genética , Genes Recessivos , Mutação/genética , Peptídeo Sintases/genética , Sequência de Aminoácidos , Animais , Vias Biossintéticas , Cardiomiopatia Dilatada/diagnóstico , Carnitina/análogos & derivados , Carnitina/metabolismo , Pré-Escolar , Coenzima A/biossíntese , Demografia , Drosophila , Estabilidade Enzimática , Feminino , Fibroblastos/metabolismo , Coração/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Panteteína/administração & dosagem , Panteteína/análogos & derivados , Linhagem , Peptídeo Sintases/sangue , Peptídeo Sintases/química , Peptídeo Sintases/deficiência , Reprodutibilidade dos Testes , Saccharomyces cerevisiae/genética
2.
Biochem Biophys Res Commun ; 437(3): 397-402, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-23831470

RESUMO

Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica , Mediadores da Inflamação/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Quimiocina CXCL1/biossíntese , Ciclo-Oxigenase 2/biossíntese , Progressão da Doença , Feminino , Fibroblastos/metabolismo , Humanos , Mediadores da Inflamação/fisiologia , Interleucina-6/biossíntese , NF-kappa B/biossíntese , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Estudos Retrospectivos , Transdução de Sinais/genética , Células Estromais/metabolismo , Células Estromais/patologia
3.
Sci Rep ; 13(1): 20513, 2023 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-37993670

RESUMO

Disruption of intestinal epithelial functions is linked to Crohn disease (CD) pathogenesis. We identified a widespread reduction in the expression of long non-coding RNAs (lncRNAs) including LHFPL3-AS2 in the treatment-naïve CD ileum of the RISK pediatric cohort. We validated the reduction of LHFPL3-AS2 in adult CD and noted a further reduction in patients with more severe CD from the RISK cohort. LHFPL3-AS2 knockdown in Caco-2 cells robustly affected epithelial monolayer morphogenesis with markedly reduced confluency and spreading, showing atypical rounding, and clumping. mRNA-seq analysis of LHFPL3-AS2 knockdown cells highlighted the reduction of genes and pathways linked with apical polarity, actin bundles, morphogenesis, and the b-catenin-TCF4 complex. LHFPL3-AS2 knockdown significantly reduced the ability of cells to form an internal lumen within the 3-dimensional (3D) cyst model, with mislocalization of actin and adherent and tight junction proteins, affecting epithelial polarity. LHFPL3-AS2 knockdown also resulted in defective mitotic spindle formation and consequent reduction in epithelial proliferation. Altogether, we show that LHFPL3-AS2 reduction affects epithelial morphogenesis, polarity, mitotic spindle formation, and proliferation, which are key processes in maintaining epithelial homeostasis in CD. Reduced expression of LHFPL3-AS2 in CD patients and its further reduction with ileal ulceration outcome, emphasizes its significance in this context.


Assuntos
Doença de Crohn , RNA Longo não Codificante , Adulto , Humanos , Criança , Células CACO-2 , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Doença de Crohn/genética , Actinas/genética , Proliferação de Células/genética , Íleo/metabolismo , Linhagem Celular Tumoral
4.
Elife ; 102021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34169837

RESUMO

Mortality from breast cancer is almost exclusively a result of tumor metastasis, and lungs are one of the main metastatic sites. Cancer-associated fibroblasts are prominent players in the microenvironment of breast cancer. However, their role in the metastatic niche is largely unknown. In this study, we profiled the transcriptional co-evolution of lung fibroblasts isolated from transgenic mice at defined stage-specific time points of metastases formation. Employing multiple knowledge-based platforms of data analysis provided powerful insights on functional and temporal regulation of the transcriptome of fibroblasts. We demonstrate that fibroblasts in lung metastases are transcriptionally dynamic and plastic, and reveal stage-specific gene signatures that imply functional tasks, including extracellular matrix remodeling, stress response, and shaping the inflammatory microenvironment. Furthermore, we identified Myc as a central regulator of fibroblast rewiring and found that stromal upregulation of Myc transcriptional networks is associated with disease progression in human breast cancer.


Assuntos
Fibroblastos/patologia , Neoplasias Pulmonares/secundário , Pulmão/patologia , Transcriptoma , Microambiente Tumoral/genética , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Camundongos , Camundongos Transgênicos
5.
Cell Syst ; 2(3): 172-84, 2016 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-27135363

RESUMO

The genomic and transcriptomic landscapes of breast cancer have been extensively studied, but the proteomes of breast tumors are far less characterized. Here, we use high-resolution, high-accuracy mass spectrometry to perform a deep analysis of luminal-type breast cancer progression using clinical breast samples from primary tumors, matched lymph node metastases, and healthy breast epithelia. We used a super-SILAC mix to quantify over 10,000 proteins with high accuracy, enabling us to identify key proteins and pathways associated with tumorigenesis and metastatic spread. We found high expression levels of proteins associated with protein synthesis and degradation in cancer tissues, accompanied by metabolic alterations that may facilitate energy production in cancer cells within their natural environment. In addition, we found proteomic differences between breast cancer stages and minor differences between primary tumors and their matched lymph node metastases. These results highlight the potential of proteomic technology in the elucidation of clinically relevant cancer signatures.


Assuntos
Neoplasias da Mama , Homeostase , Humanos , Metástase Linfática , Espectrometria de Massas , Proteômica
6.
PLoS One ; 8(2): e57160, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23451174

RESUMO

Vasculogenic mimicry (VM) describes functional vascular channels composed only of tumor cells and its presence predicts poor prognosis in melanoma patients. Inhibition of this alternative vascularization pathway might be of clinical importance, especially as several anti-angiogenic therapies targeting endothelial cells are largely ineffective in melanoma. We show the presence of VM structures histologically in a series of human melanoma lesions and demonstrate that cell cultures derived from these lesions form tubes in 3D cultures ex vivo. We tested the ability of nicotinamide, the amide form of vitamin B3 (niacin), which acts as an epigenetic gene regulator through unique cellular pathways, to modify VM. Nicotinamide effectively inhibited the formation of VM structures and destroyed already formed ones, in a dose-dependent manner. Remarkably, VM formation capacity remained suppressed even one month after the complete withdrawal of Nicotimamid. The inhibitory effect of nicotinamide on VM formation could be at least partially explained by a nicotinamide-driven downregulation of vascular endothelial cadherin (VE-Cadherin), which is known to have a central role in VM. Further major changes in the expression profile of hundreds of genes, most of them clustered in biologically-relevant clusters, were observed. In addition, nicotinamide significantly inhibited melanoma cell proliferation, but had an opposite effect on their invasion capacity. Cell cycle analysis indicated moderate changes in apoptotic indices. Therefore, nicotinamide could be further used to unravel new biological mechanisms that drive VM and tumor progression. Targeting VM, especially in combination with anti-angiogenic strategies, is expected to be synergistic and might yield substantial anti neoplastic effects in a variety of malignancies.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , Melanoma/irrigação sanguínea , Neovascularização Patológica , Niacinamida/farmacologia , Vasos Sanguíneos/crescimento & desenvolvimento , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Perfilação da Expressão Gênica , Humanos , Melanoma/genética , Melanoma/patologia , Invasividade Neoplásica
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