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1.
Exp Oncol ; 44(2): 137-141, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35964641

RESUMO

BACKGROUND: Chemokine (C-C motif) receptor 7 (CCR7) is a chemokine receptor involved in the carcinogenesis of several types of tumors due to its promoting action in epithelial-mesenchymal transition events, invasion, angiogenesis and metastasis. However, its role in prostate cancer (PCa) remains unclear. AIM: To evaluate CCR7 expression by immunohistochemistry in prostate tumors from young patients and to determine the possible relationship with the clinicopathological characteristics. MATERIALS AND METHODS: We analyzed retrospectively paraffin-embedded tissue sections from 23 young PCa (≤ 55 years old) patients and evaluated the transcriptomic expression in the TCGA database. RESULTS: Expression of CCR7 was observed in 15 cases (65%). The tissue samples from younger patients (≤ 50 years) were mostly positive in 72.7% (8/11) of cases. High grade GS (≥ 3) tumors were CCR7-positive in 71% cases. The malignant cells present in lymph nodes were CCR7 positive in 100% cases. The bioinformatic analysis showed a high CCR7 expression associated with the presence of metastasis (FC = 2.6, p = 0.03) in the Cancer Genome Atlas (TCGA) PCa cohort (PRAD). CONCLUSION: We showed that CCR7 expression in tumors from young patients is associated with the early onset of the disease and could also be related to lymph node metastasis.


Assuntos
Neoplasias da Próstata , Receptores CCR7/metabolismo , Quimiocinas/genética , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Receptores CCR7/genética , Estudos Retrospectivos
2.
Sci Rep ; 7: 40901, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28102354

RESUMO

During kidney transplantation, ischemia-reperfusion injury (IRI) induces oxidative stress. Short-term preoperative 30% dietary restriction (DR) and 3-day fasting protect against renal IRI. We investigated the contribution of macronutrients to this protection on both phenotypical and transcriptional levels. Male C57BL/6 mice were fed control food ad libitum, underwent two weeks of 30%DR, 3-day fasting, or received a protein-, carbohydrate- or fat-free diet for various periods of time. After completion of each diet, renal gene expression was investigated using microarrays. After induction of renal IRI by clamping the renal pedicles, animals were monitored seven days postoperatively for signs of IRI. In addition to 3-day fasting and two weeks 30%DR, three days of a protein-free diet protected against renal IRI as well, whereas the other diets did not. Gene expression patterns significantly overlapped between all diets except the fat-free diet. Detailed meta-analysis showed involvement of nuclear receptor signaling via transcription factors, including FOXO3, HNF4A and HMGA1. In conclusion, three days of a protein-free diet is sufficient to induce protection against renal IRI similar to 3-day fasting and two weeks of 30%DR. The elucidated network of common protective pathways and transcription factors further improves our mechanistic insight into the increased stress resistance induced by short-term DR.


Assuntos
Restrição Calórica , Dieta com Restrição de Proteínas , Rim/metabolismo , Animais , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Proteína HMGA1a/genética , Proteína HMGA1a/metabolismo , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Análise de Componente Principal , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transcriptoma
3.
Nature ; 537(7620): 427-431, 2016 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-27556946

RESUMO

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1∆/-) show numerous accelerated ageing features that limit their lifespan to 4-6 months. They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg-/- (also known as Ercc5-/-) mice, a model of Cockayne syndrome, responded similarly. The dietary restriction response in Ercc1∆/- mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1∆/- mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of γH2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1∆/- mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general.


Assuntos
Envelhecimento/genética , Restrição Calórica , Reparo do DNA/genética , Dieta Redutora , Instabilidade Genômica , Animais , Encéfalo/fisiologia , Dano ao DNA , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Endonucleases/deficiência , Endonucleases/genética , Feminino , Masculino , Camundongos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/prevenção & controle , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Transcriptoma
4.
DNA Repair (Amst) ; 12(11): 982-92, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24075570

RESUMO

DNA damage and ageing share expression changes involving alterations in many aspects of metabolism, suppression of growth and upregulation of defence and genome maintenance systems. "Omics" technologies have permitted large-scale parallel measurements covering global cellular constituents and aided the identification of specific response pathways that change during ageing and after DNA damage. We have set out to identify genes with highly conserved response patterns through meta-analysis of mRNA expression datasets collected during natural ageing and accelerated ageing caused by a Transcription-Coupled Nucleotide Excision Repair (TC-NER) defect in a diverse set of organs and tissues in mice, and from in vitro UV-induced DNA damage in a variety of murine cells. The identified set of genes that show similar expression patterns in response to organ ageing (accelerated and normal), and endogenously and exogenously induced DNA damage, consists of genes involved in anti-oxidant systems and includes the transcription factor Bach2 as one of the most consistent markers. BACH2 was originally identified as a partner of the small Maf proteins and antagonist of the NRF2 anti-oxidant defence pathway and has been implicated in B-cell differentiation and immune system homeostasis. Although BACH2 has never before been associated with UV-induced damage or ageing, it shows a strong downregulation in both conditions. We have characterized the dynamics of Bach2 expression in response to DNA damage and show that it is a highly sensitive responder to transcription-blocking DNA lesions. Gene expression profiling using Affymetrix microarray analysis after siRNA-mediated silencing of Bach2 identified cell cycle and transcription regulation as the most significantly altered processes consistent with a function as transcription factor affecting proliferation.


Assuntos
Envelhecimento/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Dano ao DNA/genética , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Biomarcadores , Sobrevivência Celular/genética , Regulação da Expressão Gênica , Células HEK293 , Humanos , Camundongos , Modelos Animais , Células NIH 3T3 , Análise de Sequência com Séries de Oligonucleotídeos , Radiação Ionizante , Raios Ultravioleta
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