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1.
Rev. Ciênc. Méd. Biol. (Impr.) ; 20(4): 526-532, fev 11, 2022. tab
Article in Portuguese | LILACS | ID: biblio-1359308

ABSTRACT

Introdução: embora o câncer seja um dos maiores problemas de saúde pública enfrentados mundialmente, diversas substâncias presentes no meio, como os fármacos, não estão muito bem elucidadas sobre seu possível potencial carcinogênico. Entre eles, estão os benzodiazepínicos, fármacos que possuem crescente aumento do consumo desde o século XX e, principalmente, na segunda década do século XXI, por suas ações ansiolíticas, sedativas e anticonvulsivantes. Objetivo: avaliar o efeito carcinogênico do bromazepam por meio do teste para detecção de tumores epiteliais (ETT) em Drosophila melanogaster. Metodologia: para realização do ETT foram utilizadas duas linhagens mutantes de D. melanogaster: wts (fêmeas) e mwh (machos). As larvas descendentes desse cruzamento foram tratadas isoladamente com cinco concentrações de bromazepam, sendo elas: 0,0375; 0,075; 0,15; 0,30 e 0,60 mM. A Doxorrubicina foi utilizada como controle positivo e a água ultrapura como controle negativo. Após tratamento, coleta e armazenamento, as moscas foram analisadas, identificando-se as frequências tumorais, por região corporal, em cada concentração testada. Resultados: o bromazepam não apresentou efeito carcinogênico em nenhuma das concentrações experimentadas neste estudo, não havendo diferença estatisticamente significativa nas frequências tumorais observadas nos indivíduos tratados com bromazepam quando comparadas à frequência obtida nos indivíduos tratados com o controle negativo. Conclusão: Nas presentes condições experimentais, o bromazepam não apresentou atividade carcinogênica, no entanto, há a necessidade de novos estudos, com diferentes metodologias e diferentes organismos testes, para a maior compreensão da ação do bromazepam no organismo.


Introduction: although cancer is one of the biggest public health problems faced worldwide, several substances present in the environment, such as drugs are not very well understood about its possible carcinogenic potential. Among them are benzodiazepines, drugs that have increased their consumption since the 20th century and, mainly, in the second decade of the 21st century, due to their anxiolytic, sedative and anticonvulsant actions. Objective: Evaluate the carcinogenic effect of bromazepam through the test to detect epithelial tumor clones (ETT) in Drosophila melanogaster. Methodology: to perform the ETT, two mutant strains of D. melanogaster were used: wts (female) and mwh (male). The descending larves of this cross were treated separately with five concentrations of bromazepam, namely: 0.0375; 0.075; 0.15; 0.30 and 0.60 mM. Doxorubicin was used as a positive control and ultrapure water as a negative control. After treatment, collection and storage, the flies were analyzed, identifying the tumor frequencies, by body region, at each concentration tested. Results: bromazepam did not have a carcinogenic effect at any of the concentrations experienced in this study, with no statistically significant difference in tumor frequencies observed in individuals treated with bromazepam when compared to the frequency obtained in individuals treated with the negative control. Conclusion: In the present experimental conditions, bromazepam did not show carcinogenic activity, however, there is a need for further studies with different methodologies and different test organisms to better understand the action of bromazepam in the body.


Subject(s)
Animals , Male , Female , Bromazepam , Carcinoma , Drosophila melanogaster , Carcinogenesis , Larva , Epithelium
2.
Rev. ADM ; 78(5): 258-263, sept.-oct. 2021. ilus, tab
Article in Spanish | LILACS | ID: biblio-1344709

ABSTRACT

Introducción: La displasia epitelial oral (DEO) es la presencia de alteraciones celulares y tisulares, lo que puede significar una etapa anterior al desarrollo del cáncer. Múltiples marcadores han sido considerados para estimar su potencial neoplásico y evolución a carcinoma, incluyendo a la molécula p53, se considera como participe de diversos fenómenos de la homeostasis celular. Objetivo: Determinar la relación entre la inmunoexpresión de p53 DO-7 y PAb 240 con el grado de severidad de la displasia epitelial oral. Material y métodos: Se analizaron nueve muestras de DEO (tres para cada grado de severidad). La inmunoexpresión de p53 tipo silvestre (DO-7) y forma mutada (PAb 240), fue determinada a través de ensayo de inmunohistoquímica por peroxidasa. Se obtuvieron la media y desviación estándar y se realizó la prueba χ2 (p < 0.05). Resultados: La edad media fue de 65.7 ± 11.4 años, la zona anatómica con mayor presencia de DEO es el borde lateral de la lengua. Ocho de nueve muestras fueron positivas para DO-7 y solo dos para PAb 240. Conclusiones: Nuestros resultados indican que, aunque la expresión de p53 DO-7 podría estar relacionada parcialmente con la patogénesis de la displasia epitelial, no todas las displasias presentaron la forma mutada de p53 (PAb 240). Lo cual coincide con el comportamiento biológico incierto de las displasias al poder permanecer sin cambios, involucionar o transformarse


Introduction: Oral epithelial dysplasia (OED) is the presence of cellular and tissue alterations, which may mean a stage prior to the development of cancer. Multiple markers have been considered to estimate its pathogenic potential and evolution to neoplasms, including the p53 molecule, considered as participating in various phenomena of cellular homeostasis. Objective: To determine the relationship between the immunoexpression of p53 DO-7 and PAb 240 with the degree of severity of oral epithelial dysplasia. Material and methods: Nine OED samples were analyzed (three for each degree of severity). The immunoexpression of wild-type p53 (DO-7) and mutated form (PAb 240) was determined through a peroxidase immunohistochemical assay. The mean and standard deviation were obtained, and χ2 test (p < 0.05) were performed. Results: The mean age was 65.7 ± 11.4 years, with a greater presence of OED in the anatomical area of the lateral side of the tongue. Eight out of nine samples were positive for DO-7 and only two for PAb 240. Conclusions: Our results indicate that, although the expression of p53 DO-7 could be partially related to the pathogenesis of epithelial dysplasia, not all dysplasias presented the mutated form of p53 (PAb 240), which coincides that not all dysplasias have a potential for malignant transformation and that could be related to other oncogenic mechanisms (AU)


Subject(s)
Humans , Male , Female , Child , Adolescent , Adult , Middle Aged , Aged , Precancerous Conditions , Immunohistochemistry , Genes, p53 , Gingival Neoplasms , Tongue Neoplasms , Pilot Projects , Statistical Analysis , Carcinogenesis , Observational Study , Mexico
3.
Rev. cuba. invest. bioméd ; 40(1): e989, ene.-mar. 2021. graf
Article in Spanish | LILACS, CUMED | ID: biblio-1289447

ABSTRACT

Introducción: Los ácidos biliares en condiciones no fisiológicas se consideran agentes inflamatorio-carcinógenos endógenos que originan alteraciones en membranas plasmáticas, mitocondrias, el ADN, los genes y, la apoptosis de las células epiteliales. Objetivo: Describir la asociación entre los niveles elevados de ácidos biliares en la luz intestinal y la secuencia inflamación-cáncer, expresados como lesiones inflamatorias, premalignas y malignas del tracto digestivo. Métodos: Revisión sistemática y crítica de las evidencias sobre los mecanismos biomoleculares asociados a niveles altos de ácidos biliares en la luz intestinal y la secuencia inflamación-carcinogénesis, en bases de datos como PubMed, Medline, SciELO, LILACS y Elsevier, publicados entre 2015-2020, que establecen el fundamento teórico y metabolómico de dicha secuencia. Resultados: Los ácidos biliares tienen una acción tóxica en la secuencia inflamación-cáncer del tracto digestivo, al perderse el control de su homeostasis o la integridad anatomo-funcional del sistema hepato-vesículo-bilio-intestinal. Conclusiones: Los mecanismos celulares y biomoleculares desencadenados por los niveles altos de ácidos biliares contextualizan la génesis del proceso secuencial inflamación-cáncer y su interacción con los factores de riesgo clásicos, genéticos y epigenéticos reconocidos como un nuevo paradigma fisiopatológico del cáncer digestivo(AU)


Introduction: In non-physiological conditions, bile acids (BA) are considered to be endogenous inflammatory-carcinogenic agents causing alterations in plasma membranes, mitochondria, DNA, genes and epithelial cell apoptosis. Objective: Describe the association between high bile acid levels in the intestinal lumen and the inflammation-cancer sequence, expressed as inflammatory premalignant and malignant lesions of the digestive tract. Methods: A systematic critical review was conducted of the evidence about biomolecular mechanisms associated to high bile acid levels in the intestinal lumen and the inflammation-carcinogenesis sequence published in the databases PubMed, Medline, SciELO, LILACS and Elsevier in the period 2015-2020, laying the theoretical and metabolomic foundations of that sequence. Results: Bile acids display toxic activity in the inflammation-cancer sequence of the digestive tract, since control is lost of its homeostasis or the anatomical-functional integrity of the hepato-vesicular-biliary-intestinal system. Conclusions: The cellular and biomolecular mechanisms triggered by high bile acid levels provide a context for the genesis of the inflammation-cancer sequential process and its interaction with the classic, genetic and epigenetic risk factors recognized as a new pathophysiological paradigm of digestive cancer(AU)


Subject(s)
Humans , Male , Female , Bile Acids and Salts/toxicity , Gastrointestinal Tract/pathology , Carcinogenesis/pathology , Inflammation , Risk Factors
4.
Braz. j. med. biol. res ; 54(9): e10931, 2021. tab, graf
Article in English | LILACS | ID: biblio-1249340

ABSTRACT

Tobacco can induce reactive oxygen species (ROS) production extensively in cells, which is a major risk factor for oral leukoplakia (OLK) development. Peroxiredoxin 1 (Prx1) is a key antioxidant protein, upregulated in a variety of malignant tumors. We previously found that nicotine, the main ingredient of tobacco, promotes oral carcinogenesis via regulating Prx1. The aim of the present study was to screen and identify the Prx1 interacting proteins and investigate the mechanisms of nicotine on the development of OLK. Through liquid chromatography-tandem mass spectrometry combined with bioinformatics analysis, the candidate Prx1 interacting proteins of cofilin-1 (CFL1), tropomyosin alpha-3 chain (TPM3), and serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) were screened in human dysplastic oral keratinocyte cells treated with nicotine. CFL1, TPM3, and PPP2R1A were highly expressed in human OLK tissues. The expression of CFL1 increased and the expression of PPP2R1A decreased in OLK of smokers compared to that in OLK of non-smokers. Nicotine upregulated CFL1 and downregulated PPP2R1A in 4-nitro-quinoline-1-oxide (4NQO)-induced OLK tissues in mice in part dependent on Prx1. Furthermore, the in-situ interaction of CFL1, TPM3, and PPP2R1A with Prx1 were validated in human OLK tissues. Our results suggested that tobacco might promote the development of OLK via regulating Prx1 and its interacting proteins CFL1 and PPP2R1A.


Subject(s)
Animals , Mice , Leukoplakia, Oral/chemically induced , Peroxiredoxins/metabolism , Nicotine , Carrier Proteins , Homeodomain Proteins , Carcinogenesis
5.
Braz. j. med. biol. res ; 54(5): e10637, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153548

ABSTRACT

Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.


Subject(s)
Humans , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Carcinogenesis/genetics , Signal Transduction , Cell Differentiation , Cell Transformation, Neoplastic/genetics
6.
São Paulo; s.n; 2021. 87 p. tab, ilus.
Thesis in Portuguese | LILACS, Inca | ID: biblio-1348764

ABSTRACT

Um dos principais pontos de controle da tradução de mRNAs ocorre através da fosforilação da subunidade alfa do fator de início de tradução eIF2 (eIF2α), o que leva à inibição da síntese geral de proteínas. GCN2 é uma das quinases de eIF2α que responde à carência de aminoácidos e radiação UV, fosforilando eIF2α e inibindo a tradução geral. Sua atividade depende da união com a proteína GCN1. A proteína IMPACT também interage com GCN1, competindo pela ligação GCN1-GCN2, inibindo a atividade de GCN2 e estimulando a tradução. Através de pesquisas em bancos de dados utilizando o cBioPortal, observamos que em adenocarcinomas de pâncreas, existem alterações nos genes que codificam IMPACT, GCN1 e GCN2 em uma porcentagem significativa de casos. No Brasil, este tumor é responsável por cerca de 2% de todos os tipos de câncer diagnosticados e por 4% do total de mortes por câncer. Devido à natureza agressiva da doença e ao diagnóstico tardio, a maioria dos pacientes apresenta o câncer localmente avançado ou metastático, possuindo uma alta taxa de mortalidade e sobrevida de 5 anos menor que 7%. Portanto, desvendar mecanismos moleculares associados a este tumor é de extrema importância para o desenvolvimento de novas abordagens terapêuticas. Utilizando um modelo celular de adenocarcinoma de pâncreas, nocaute para IMPACT, realizamos ensaios funcionais. eIF2 foi mais fosforilado pelas linhagens nocautes na avaliação por estresse a UV, mas não para privação de leucina. Além disso, células nocautes também apresentaram menor capacidade de formar colônias independentemente de ancoragem, e menos formação tumoral nos ensaios em vivo, além de apresentarem menor capacidade de formar e manter estruturas 3D avaliadas no ensaio de esferoides e adesão. A partir da avaliação dos Tissue Micro Arrays (TMAs), tumores primários apresentaram maior quantidade de IMPACT quando comparados com tumores metastáticos e tecido normal. Interessantemente, tanto no TMA quanto nas linhagens celulares foram observados grânulos de IMPACT tanto no núcleo quanto no citoplasma e associados a proteínas características de grânulos de estresse e proteínas do nucléolo. Diante dos resultados encontrados, podemos concluir que a proteína IMPACT pode ter atuação no ciclo celular além de fazer parte de grânulos de estresse. Além disso, levanta-se a hipótese que pode atuar em dois momentos na progressão tumoral: um primeiro momento onde a superexpressão favoreceria a sobrevivência do tumor e um segundo momento onde a diminuição de IMPACT facilitaria a metástase. Portanto o estudo dessa proteína pode melhorar o entendimento não só dos mecanismos envolvidos no desenvolvimento e progressão do Adenocarcinoma de Pâncreas, mas também de processos biológicos relacionados com outros tumores e até mesmo outras doenças.


Subject(s)
Humans , Male , Female , Aged , Pancreatic Neoplasms , Carcinogenesis , Carcinoma, Pancreatic Ductal
7.
Article in English | WPRIM | ID: wpr-879958

ABSTRACT

The primary cilium, a sensory organelle that protrudes from the surface of most eukaryotic cells, receives and transduces various critical signals that are essential for normal development and homeostasis. Structural or functional disruption of primary cilia causes a number of human diseases, including cancer. Primary cilia has cross talks with cell cycle and it may act as a cell cycle checkpoint to suppress cancer development. Moreover, primary cilia has cross-regulation with autophagy, which may affect tumor progression. We then discuss the association of the primary cilia with several oncogenic signaling pathways, including Shh, Wnt, Notch and platelet-derived growth factor receptor (PDGFR). Since these signaling pathways are often over-activated in many types of human cancers, primary cilia are likely to play a role in the tumorigenesis by modulating these pathways. Finally, we summarize current progress on the role of cilia during tumorigenesis and the challenges that the cilia-cancer field faces.


Subject(s)
Autophagy , Carcinogenesis , Cilia , Homeostasis , Humans , Signal Transduction
8.
Article in English | WPRIM | ID: wpr-879956

ABSTRACT

Epigenetics concerns gene regulatory mechanisms beyond DNA sequence,such as DNA methylation,histone modification,chromatin remodeling,and non-coding RNA. Epigenetic mechanisms play a key role in development,cell fate decision and tumorigenesis. Chromatin modifications and its high order structure across our genome are major forms of epigenetic information,and its establishment and maintenance are closely related to cell metabolism. Metabolic changes in cancer cells include aerobic glycolysis,increased glucose uptake,abnormally active glutamine metabolism,and the use of non-conventional energy supply. These changes meet the vigorous energy and matter needs for the development and spread of cancer,and help tumor cells adapt to hypoxia microenvironment for their survival,proliferation,invasion and migration. There is a complex relationship between epigenetic modifications and cell metabolism in tumor. On the one hand,metabolites in tumor cells may act as cofactors,modification donors or antagonists of epigenetic enzymes,thus modulating the epigenetic landscape. On the other hand,epigenetic modifications can directly regulate the expression of metabolic enzymes,transporters,signaling pathway and transcription factors to affect cell metabolism. This article reviews the crosstalk between epigenetics and cancer metabolism,to explore their potential future applications in the treatment of tumors.


Subject(s)
Carcinogenesis , DNA Methylation , Epigenesis, Genetic , Gene Expression Regulation , Humans , Neoplasms/genetics , Tumor Microenvironment
9.
Article in English | WPRIM | ID: wpr-922690

ABSTRACT

SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF) plays dual roles in the initiation and development of human malignancies. However, the biological role of SPDEF in head and neck squamous cell carcinoma (HNSCC) remains unclear. In this study, the expression level of SPDEF and its correlation with the clinical parameters of patients with HNSCC were determined using TCGA-HNSC, GSE65858, and our own clinical cohorts. CCK8, colony formation, cell cycle analysis, and a xenograft tumor growth model were used to determine the molecular functions of SPDEF in HNSCC. ChIP-qPCR, dual luciferase reporter assay, and rescue experiments were conducted to explore the potential molecular mechanism of SPDEF in HNSCC. Compared with normal epithelial tissues, SPDEF was significantly downregulated in HNSCC tissues. Patients with HNSCC with low SPDEF mRNA levels exhibited poor clinical outcomes. Restoring SPDEF inhibited HNSCC cell viability and colony formation and induced G0/G1 cell cycle arrest, while silencing SPDEF promoted cell proliferation in vitro. The xenograft tumor growth model showed that tumors with SPDEF overexpression had slower growth rates, smaller volumes, and lower weights. SPDEF could directly bind to the promoter region of NR4A1 and promoted its transcription, inducing the suppression of AKT, MAPK, and NF-κB signaling pathways. Moreover, silencing NR4A1 blocked the suppressive effect of SPDEF in HNSCC cells. Here, we demonstrate that SPDEF acts as a tumor suppressor by transcriptionally activating NR4A1 in HNSCC. Our findings provide novel insights into the molecular mechanism of SPDEF in tumorigenesis and a novel potential therapeutic target for HNSCC.


Subject(s)
Carcinogenesis , Cell Proliferation , Head and Neck Neoplasms , Humans , Nuclear Receptor Subfamily 4, Group A, Member 1 , Proto-Oncogene Proteins c-ets , Squamous Cell Carcinoma of Head and Neck , Transcription Factors
10.
Article in English | WPRIM | ID: wpr-878404

ABSTRACT

OBJECTIVES@#To study the hypoxia response gene and microRNA (miRNA) expression profiles in the pathogenesis and progression of oral leukoplakia (OLK).@*METHODS@#Affymetrix GeneChip human transcriptome array 2.0 was used to detect the transcriptome of normal mucosa, low-risk OLK, high-risk OLK, and early squamous cell carcinoma (SCC). Gene ontology function analysis was used to screen genes and key miRNAs whose biological role is hypoxia response. Quantitative reverse transcription polymerase ch-ain reaction (qRT-PCR) was used to verify the expression of hypoxia response genes and miRNAs.@*RESULTS@#A total of 7 different genes of hypoxia response between normal mucosa and low-risk OLK, 10 genes between low-risk and high-risk OLK, and 21 genes between high-risk OLK and SCC were identified. The results of qRT-PCR showed that the expression of hypoxia-inducible factor 1α, chemokine cc-motif ligand 2, and matrix metalloproteinase 3 mRNA and miR-21 in normal mucosa, OLK, and SCC increased in a stepwise manner. The expression difference between OLK and SCC was statistically significant and consistent with the results of transcriptome array.@*CONCLUSIONS@#The hypoxia response gene and related miRNA play roles in the development and progression of OLK.


Subject(s)
Carcinogenesis , Humans , Hypoxia , Leukoplakia, Oral , MicroRNAs , Mouth Neoplasms , Transcriptome
11.
Chinese Medical Journal ; (24): 1017-1030, 2021.
Article in English | WPRIM | ID: wpr-878138

ABSTRACT

The LIM domain only 1 (LMO1) gene belongs to the LMO family of genes that encodes a group of transcriptional cofactors. This group of transcriptional cofactors regulates gene transcription by acting as a key "connector" or "scaffold" in transcription complexes. All LMOs, including LMO1, are important players in the process of tumorigenesis. Unique biological features of LMO1 distinct from other LMO members, such as its tissue-specific expression patterns, interacting proteins, and transcriptional targets, have been increasingly recognized. Studies indicated that LMO1 plays a critical oncogenic role in various types of cancers, including T-cell acute lymphoblastic leukemia, neuroblastoma, gastric cancer, lung cancer, and prostate cancer. The molecular mechanisms underlying such functions of LMO1 have also been investigated, but they are currently far from being fully elucidated. Here, we focus on reviewing the current findings on the role of LMO1 in tumorigenesis, the mechanisms of its oncogenic action, and the mechanisms that drive its aberrant activation in cancers. We also briefly review its roles in the development process and non-cancer diseases. Finally, we discuss the remaining questions and future investigations required for promoting the translation of laboratory findings to clinical applications, including cancer diagnosis and treatment.


Subject(s)
Carcinogenesis/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Neoplastic , Humans , LIM Domain Proteins/genetics , Male , Transcription Factors/metabolism
12.
Chinese Journal of Biotechnology ; (12): 3789-3800, 2021.
Article in Chinese | WPRIM | ID: wpr-921465

ABSTRACT

Lung microbiota and gut microbiota are closely related to lung cancer. Studies have shown that the dysbiosis, i.e., the significantly altered composition and structure of gut and lung microbiota, usually occurs in patients with lung cancer. With the introduction of "Gut-Lung Axis", an increasing attention has been paid to the close relationship between the lung and gut microbiota in human body. A deeper insight into this relationship would facilitate understanding the mechanisms behind the carcinogenesis and development of lung cancer. This article summarizes the composition of lung and gut microbiota in patients with lung cancer and the possible interaction mechanisms, highlighting the importance of the immune system in the Gut-Lung Axis. The effects of lung and gut microbiota on the clinical treatment of lung cancer were summarized, based on which the authors propose that the lung and gut microbiota can be used as novel targets for early diagnosis and treatment of lung cancer.


Subject(s)
Carcinogenesis , Dysbiosis , Gastrointestinal Microbiome , Humans , Lung , Lung Neoplasms
13.
Article in English | WPRIM | ID: wpr-880659

ABSTRACT

Epstein-Barr virus (EBV), a definite tumorigenic virus, is closely related to the development of nasopharyngeal cancer, gastric cancer, lymphoma and other tumors. EBV encodes a total of 44 mature microRNAs, which can regulate the expression of virus and host genes. EBV-encoded microRNAs and their regulated target molecules participate in the biological functions of tumor apoptosis, proliferation, invasion, and metastasis during tumorigenesis and development, and play an important role in the development of tumor.


Subject(s)
Carcinogenesis/genetics , Epstein-Barr Virus Infections/genetics , Gene Expression Regulation, Neoplastic , Herpesvirus 4, Human/genetics , Humans , MicroRNAs/genetics , Nasopharyngeal Neoplasms/genetics
14.
Braz. j. biol ; 80(3): 484-496, July-Sept. 2020. graf
Article in English | LILACS | ID: biblio-1132402

ABSTRACT

Abstract The main objective of current study was to investigate the chemopreventive and chemotherapeutic activity of Artemisia vulgaris extract on diethylnitrosoamine induced hepatocarcinogenesis in Balb C mice. Diethylnitrosoamine (DEN: 0.9%) was prepared to induce hepatocarcinoma in Balb C mice. The extract Artemisia vulgaris (AV) was prepared by maceration technique. Mice were classified into four groups as follows: Group 1 a control group (N=7) received saline solution (3.5 μl/mg), group 2 (N=14) received diethylnitrosoamine (3.5 μl/mg) intraperitoneally once in a week for eight consecutive weeks, group 3 (N=7) received only plant extract (AV: 150 mg/kg (Body weight) once in a week, while group 4 (N=7) was given in combination of diethylnitrosoamine (3.5 μl/mg) and plant extract (AV: 150 mg/kg (body weight). After eight weeks of DEN administration, mice of group 2 were divided into two subgroups containing seven mice each; subgroup 1 was sacrificed while subgroup 2 was treated with plant extract only (150 mg/kg (body weight)) once in a week for eight consecutive weeks. The DEN injected mice significant decline in levels of albumin with concomitant significant elevations such as aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, alpha feto protein, gamma glutamyl transferase, 5 nucleotidase, glucose-6-phosphate dehydrogenase and bilirubin. The administration of A. vulgaris significantly decreased the DEN induced hepatotoxicity. Present study revealed the potential anti-cancerous nature of Artemisia vulgaris, both in case of chemopreventive and post-treatment of A. vulgaris. Further studies are needed to explore the mechanism of prevention and therapy.


Resumo O objetivo principal do presente estudo foi investigar as atividades quimiopreventiva e quimioterápica do extrato de Artemisia vulgaris em hepatocarcinogênese induzida por dietilnitrosoamina (DEN) em camundongos Balb C. Dietilnitrosoamina (DEN: 0,9%) foi preparada para induzir hepatocarcinoma em camundongos da linhagem Balb C. O extrato de A. vulgaris (AV) foi preparado pela técnica de maceração. Os camundongos foram classificados em quatro grupos conforme os seguintes: grupo 1, grupo controle (N=7) recebeu solução salina (3,5 µl/mg); grupo 2 (N=14) recebeu dietilnitrosoamina (3,5 µl/mg) por via intraperitoneal uma vez por semana durante oito semanas consecutivas; grupo 3 (N=7) recebeu apenas o extrato vegetal (AV: 150 mg/kg (peso corporal) uma vez por semana; enquanto no grupo 4 (N=7) foi administrado uma combinação de dietilnitrosoamina (3,5 μl/mg) com extrato vegetal (AV: 150 mg/kg (peso corporal). Após oito semanas de administração de DEN, os camundongos do grupo 2 foram divididos em dois subgrupos, contendo sete camundongos cada um; no subgrupo 1, os animais foram sacrificados, enquanto no subgrupo 2, os animais foram tratados apenas com extrato vegetal (150 mg/kg (peso corporal)) uma vez por semana durante oito semanas consecutivas. Os camundongos nos quais foram injetados DEN apresentaram declínio significativo nos níveis de albumina, mas elevações significativas concomitantes de: aspartato aminotransferase, alanina aminotransferase, lactato desidrogenase, alfa-fetoproteína, gama-glutamiltransferase, 5' nucleotidase, glicose-6-fosfato desidrogenase e bilirrubina. A administração de A. vulgaris diminuiu significativamente a hepatotoxicidade induzida pelo DEN. O presente estudo apresentou a potencialidade anticancerosa da A. vulgaris, tanto nos casos de quimioprevenção quanto no pós-tratamento da A. vulgaris. Mais estudos são necessários para explorar o mecanismo de prevenção e a terapia.


Subject(s)
Animals , Rabbits , Carcinoma, Hepatocellular , Artemisia , Liver Neoplasms , Plant Extracts , Diethylnitrosamine , Carcinogenesis , Mice, Inbred BALB C
15.
Braz. dent. j ; 31(3): 290-297, May-June 2020. tab, graf
Article in English | LILACS, BBO | ID: biblio-1132302

ABSTRACT

Abstract Chloride intracellular channel-4 (CLIC4) is regulated by p53 and tumor necrosis factor-α (TNF-α), it is linked to the increase of transforming growth factor-β (TGF-β), and myofibroblastic differentiation in skin carcinogenesis. This study analyzed the immunoexpression of CLIC4, p53, TGF-β, TNF-α, and α-SMA in 50 actinic cheilitis (AC) and 50 lower lip squamous cell carcinoma (LLSCC). AC and LLSCC immunoexpression were categorized as score 1 (<5% positive cells), 2 (5-50%) or 3 (>50%). For CLIC4, nuclear and cytoplasmic immunostaining of epithelial cells was considered individually. For morphologic analysis, the World Health Organization criteria were used to epithelial dysplasia grade of ACs, and Bryne grading of malignancy system was applied for LLSCC. Higher nuclear CLIC4 (CLIC4n) and TGF-β were observed in ACs with low-risk of transformation, while cytoplasmic CLIC4 (CLIC4c), p53 and TNF-α were higher in the high-risk cases (p<0.05). In LLSCCs, CLIC4c was higher in cases with lymph node metastasis, advanced clinical stages, and histological high-grade malignancy. p53 expression was higher in high-grade LLSCCs, whereas TGF-β decreased as the clinical stage and morphological grade progressed (p<0.05). ACs showed an increased expression of CLIC4n and TGF-β, while CLIC4c and α-SMA were higher in LLSCCs (p<0.0001). Both lesions showed negative correlation between CLIC4n and CLIC4c, while in LLSCCs, negative correlation was also verified between CLIC4c and p53, as well as CLIC4c and TGF-β (p<0.05). Change of CLIC4 from the nucleus to cytoplasm and alterations in p53, TGF-β, TNF-α, and α-SMA expression are involved in lip carcinogenesis.


Resumo O canal intracelular de cloreto 4 (CLIC4) é regulado pela p53 e fator de necrose tumoral α (TNF-α) e está relacionado ao aumento do fator de crescimento transformador β (TGF-β) e na diferenciação miofibroblástica na carcinogênese cutânea. Este estudo analisou a imunoexpressão de CLIC4, p53, TGF-β, TNF-α e α-SMA em 50 queilites actínicas (QA) e 50 carcinomas de células escamosas de lábio inferior (CCELI). A imunoexpressão da QA e CCELI foram categorizadas em escore 1 (<5% de células positivas), 2 (5-50%) ou 3 (>50%). Para CLIC4, a imunomarcação nuclear e citoplasmática das células epiteliais foi considerada separadamente. Para análise morfológica, foram utilizados os critérios da Organização Mundial da Saúde para a gradação das displasias epiteliais nas QAs, e o sistema de gradação de malignidade de Bryne foi utilizado para os casos de CCELIs. Alta imunoexpressão de CLIC4 nuclear (CLIC4n) e TGF-β foi observada em QA de baixo risco de transformação, enquanto CLIC4 citoplasmática (CLIC4c), p53 e TNF-α foram elevadas nos casos de alto risco (p<0.05). No CCELI, a imunoexpressão de CLIC4c foi maior em caos com metástase linfonodal, estágio clínico avançado e alto grau histológico de malignidade. A expressão de p53 foi elevada em CCELI de alto grau, enquanto o TGF-β diminuiu à medida que o estádio clínico e o grau morfológico progrediram (p<0.05). QAs exibiram uma elevada expressão de CLIC4n e TGF-β, enquanto o CLIC4c e α-SMA foram elevados em CCELIs (p<0.0001). Ambas as lesões mostraram correlação negativa entre CLIC4n e CLIC4c, enquanto nos CCELIs, também se verificou correlação negativa entre CLIC4c e p53, assim como entre CLIC4c e TGF-β (p<0.05). Alteração do CLIC4 do núcleo para o citoplasma e alterações na expressão de p53, TGF-β, TNF-α, e α-SMA estão envolvidas na carcinogênese labial.


Subject(s)
Humans , Lip Neoplasms , Transforming Growth Factor beta , Tumor Suppressor Protein p53 , Tumor Necrosis Factor-alpha , Chloride Channels , Myofibroblasts , Carcinogenesis , Lip
16.
Medicina (B.Aires) ; 80(2): 127-133, abr. 2020. ilus, tab
Article in Spanish | LILACS | ID: biblio-1125052

ABSTRACT

El carcinoma escamoso vulvar puede desarrollarse de manera asociada o independiente a la infección por HPV. La relación entre la patogénesis, la clasificación, el perfil inmunohistoquímico, y el pronóstico ha sido estudiada con algunas discrepancias. El objetivo del trabajo fue observar la concordancia clásicamente descripta que asocia a los carcinomas queratinizantes con la ausencia de infección por HPV y a los carcinomas warty y basaloides con la presencia de dicho virus. Para ello, revisamos la clínica, la morfología y el inmunofenotipo de 39 casos de nuestro hospital. Los tumores fueron clasificados histológicamente en carcinomas escamosos queratinizantes clásicos (30), warty (5) y basaloides (4). En el análisis estadístico la expresión de p16 fue asociada de manera significativa con una edad menor al momento del diagnóstico (p = 0.0025), presencia de lesión intraepitelial escamosa de alto grado (p < 0.0001), coilocitosis (p = 0.02), y subtipo morfológico (p = 0.02); y fue inversamente asociado con la expresión de p53 (p < 0.0001) y con el liquen escleroso (p = 0.0051). Resulta peculiar que, de los casos estudiados, 4 carcinomas queratinizantes coexpresaron p16 y p53. Un solo tumor de tipo warty resultó negativo para p16 y positivo para p53, y 9 queratinizantes resultaron positivos para p16 y negativos para p53. Si bien estos hallazgos indican que con la sola utilización de la hematoxilina y eosina podrían definirse de manera correcta los tumores asociados al HPV, sugerimos fuertemente la realización de inmunohistoquímica, especialmente en carcinomas escamosos queratinizantes en pacientes jóvenes o con historia de HPV.


Squamous cell carcinoma of the vulva may develop in association or independently of HPV infection. The relationship between pathogenesis, classification, immunohistochemical profile and prognosis has been studied in the literature with some discrepancies. The aim of this study was to observe the classical association of keratinizing carcinomas with the absence of HPV infection and warty and basaloid carcinomas with the presence of this virus. Therefore, we reviewed the clinic, morphology, and immunophenotype of 39 cases. The tumors were histologically classified into classic keratinizing squamous carcinoma (30), warty (5) and basaloid (4). In the statistical analysis, diffuse expression with p16 was significantly associated with younger age (p = 0.0025), presence of high-grade intraepithelial lesion (p < 0.0001), koilocytosis (p = 0.02), and morphological subtype (p = 0.02), and was inversely associated with the expression of p53 (p < 0.0001) and the presence of lichen sclerosus (p = 0.0051). It is curious that 4 keratinizing carcinomas of the cases studied presented coexpression of p16 and p53. Only one warty tumor was negative for p16 and positive for p53, and 9 keratinizing tumors were positive for p16 and negative for p53. Although these findings show that the use of hematoxylin and eosin could correctly define tumors associated with HPV, we strongly suggest the performance of immunohistochemistry, especially in squamous keratinizing classic carcinomas in young patients with a history of HPV.


Subject(s)
Humans , Female , Adult , Middle Aged , Aged , Aged, 80 and over , Vulvar Neoplasms/metabolism , Immunohistochemistry , Carcinoma, Squamous Cell/metabolism , Tumor Suppressor Protein p53/metabolism , Papillomaviridae , Vulvar Neoplasms/diagnosis , Warts , Carcinoma, Squamous Cell/diagnosis , Biomarkers, Tumor , Papillomavirus Infections , Carcinogenesis
17.
Hematol., Transfus. Cell Ther. (Impr.) ; 42(1): 70-76, Jan.-Mar. 2020. tab, ilus
Article in English | LILACS | ID: biblio-1090469

ABSTRACT

Abstract Inflammation and angiogenesis are linked to the development of cancer since both can support the establishment of a tumor-prone microenvironment. The CCR5 is a major regulatory molecule involved in inflammation. The CD34 molecule is commonly described as a hematopoietic stem cell marker, and CD34+ cells are involved in the regulation of distinct physiological processes, including angiogenesis. CCR5 participates in the development of various types of cancer, and recently, a reduced CCR5 expression was associated with low CD34+ cell counts in human cord blood. A naturally occurring genetic variant of the CCR5 gene, the so-called CCR5Δ32 polymorphism, consists of a 32 base-pair deletion in the DNA, interfering in the CCR5 protein levels on the cell surface. When in homozygosis, this variant leads to a total absence of CCR5 expression on the cell surface. In heterozygous individuals, CCR5 surface levels are reduced. Based on these key findings, we hypothesize that a functional interaction can connect CCR5 and CD34 molecules (giving rise to a "CCR5-CD34 axis"). According to this, a CCR5-CD34 interaction can potentially support the development of different types of cancer. Consequently, the lack of CCR5 in association with reduced CD34+ cell counts could indicate a protective factor against the development of cancer. It is required to characterize in detail the functional relationship between CCR5 and CD34 proteins, as well as the real influence of both molecules on the susceptibility and development of cancer at population level. If our hypothesis is confirmed, the CCR5-CD34 axis may be a potential target in the development of anti-cancer therapies.


Subject(s)
Antigens, CD34 , Receptors, CCR5 , Angiogenesis Inducing Agents , Carcinogenesis , Inflammation , Neoplasms
18.
Arq. neuropsiquiatr ; 78(1): 34-38, Jan. 2020. graf
Article in English | LILACS | ID: biblio-1088980

ABSTRACT

Abstract Brain tumors are one of the most common causes of cancer-related deaths around the world. Angiogenesis is critical in high-grade malignant gliomas, such as glioblastoma multiforme. Objective: The aim of this study is to comparatively analyze the angiogenesis-related genes, namely VEGFA, VEGFB, KDR, CXCL8, CXCR1 and CXCR2 in LGG vs. GBM to identify molecular distinctions using datasets available on The Cancer Genome Atlas (TCGA). Methods: DNA sequencing and mRNA expression data for 514 brain lower grade glioma (LGG) and 592 glioblastoma multiforme (GBM) patients were acquired from The Cancer Genome Atlas (TCGA), and the genetic alterations and expression levels of the selected genes were analyzed. Results: We identified six distinct KDR mutations in the LGG patients and 18 distinct KDR mutations in the GBM patients, including missense and nonsense mutations, frame shift deletion and altered splice region. Furthermore, VEGFA and CXCL8 were significantly overexpressed within GBM patients. Conclusions: VEGFA and CXCL8 are important factors for angiogenesis, which are suggested to have significant roles during tumorigenesis. Our results provide further evidence that VEGFA and CXCL8 could induce angiogenesis and promote LGG to progress into GBM. These findings could be useful in developing novel targeted therapeutics approaches in the future.


Resumo Os tumores cerebrais são uma das causas mais comuns de mortes relacionadas ao câncer em todo o mundo. A angiogênese tem caráter crítico em gliomas malignos de alto grau, como o glioblastoma multiforme. Objetivo: O objetivo deste estudo foi analisar comparativamente os genes relacionados à angiogênese, VEGFA, VEGFB, KDR, CXCL8, CXCR1 e CXCR2 em GBG vs. GBM para identificar distinções moleculares usando conjuntos de dados disponíveis no The Cancer Genome Atlas (TCGA). Métodos: Os dados de sequenciamento de DNA e expressão de mRNA para 514 pacientes com glioma cerebral de baixo grau (GBG) e 592 pacientes com glioblastoma multiforme (GBM) foram adquiridos do TCGA e as alterações genéticas e os níveis de expressão dos genes selecionados foram analisados. Resultados: Identificamos seis mutações KDR distintas nos pacientes GBG e 18 mutações KDR distintas nos pacientes GBM, incluindo mutações missense e nonsense, exclusão de mudança de quadro e região de emenda alterada. Além disso, VEGFA e CXCL8 foram significativamente super-expressos nos pacientes com GBM. Conclusões: VEGFA e CXCL8 são fatores importantes para a angiogênese, os quais parecem ter um papel significativo durante a tumorigênese. Nossos resultados fornecem evidências adicionais de que o VEGFA e o CXCL8 podem induzir a angiogênese e promover o GBG a progredir no GBM. Esses achados podem ser úteis no desenvolvimento de novas abordagens terapêuticas direcionadas no futuro.


Subject(s)
Humans , Brain Neoplasms/genetics , Glioblastoma/genetics , Carcinogenesis/genetics , Glioma/genetics , Neovascularization, Pathologic/genetics , Reference Values , Gene Expression , Interleukin-8/analysis , Point Mutation/genetics , Glioblastoma/pathology , Receptors, Interleukin-8A/analysis , Receptors, Interleukin-8B/analysis , Vascular Endothelial Growth Factor Receptor-2/analysis , Vascular Endothelial Growth Factor A/analysis , Vascular Endothelial Growth Factor B/analysis , Glioma/pathology
19.
J. appl. oral sci ; 28: e20190532, 2020. tab, graf
Article in English | LILACS, BBO | ID: biblio-1101257

ABSTRACT

Abstract Oral leukoplakia (OL) is a white lesion of an indeterminate risk not related to any excluded (other) known diseases or disorders that carry no increased risk for cancer. Many biological markers have been used in an attempt to predict malignant transformation; however, no reliable markers have been established so far. Objective To evaluate cell proliferation and immortalization in OL, comparing non-dysplastic (Non-dys OL) and dysplastic OL (Dys OL). Methodology This is a cross-sectional observational study. Paraffin-embedded tissue blocks of 28 specimens of Non-dys OL, 33 of Dys OL, 9 of normal oral mucosa (NOM), 17 of inflammatory hyperplasia (IH), and 19 of oral squamous cell carcinomas (OSCC) were stained for Ki-67 and BMI-1 using immunohistochemistry. Results A gradual increase in BMI-1 and K-i67 expression was found in oral carcinogenesis. The immunolabeling for those markers was higher in OSCC when compared with the other groups (Kruskal-Wallis, p<0.05). Ki-67 expression percentage was higher in OL and in IH when compared with NOM (Kruskal-Wallis/Dunn, p<0.05). Increased expression of BMI-1 was also observed in OL when compared with NOM (Kruskal-Wallis/Dunn, p<0.05). No differences were observed in expression of both markers when non-dysplastic and dysplastic leukoplakias were compared. A significant positive correlation between Ki-67 and BMI-1 was found (Spearman correlation coefficient, R=0.26, p=0.01). High-grade epithelial dysplasia was associated with malignant transformation (Chi-squared, p=0.03). Conclusions These findings indicate that BMI-1 expression increases in early oral carcinogenesis and is possibly associated with the occurrence of dysplastic changes. Furthermore, our findings indicate that both Ki-67 and BMI-1 are directly correlated and play a role in initiation and progression of OSCC.


Subject(s)
Humans , Animals , Male , Adult , Middle Aged , Aged , Aged, 80 and over , Leukoplakia, Oral/pathology , Mouth Neoplasms/pathology , Carcinoma, Squamous Cell/pathology , Ki-67 Antigen/analysis , Polycomb Repressive Complex 1/analysis , Mouth Mucosa/pathology , Immunohistochemistry , Cross-Sectional Studies , Risk Factors , Statistics, Nonparametric , Disease Progression , Cell Proliferation , Carcinogenesis/pathology
20.
Clinics ; 75: e1554, 2020.
Article in English | LILACS | ID: biblio-1089608

ABSTRACT

Opioids are the main group of pharmacological agents used during the perioperative period and provide a sedative and analgesic component. The observations of opioid consumption in West Europe indicate that this group of drugs is widely used in chronic noncancer pain therapy. Nearly 20 years ago, the first publications indicating that opioids, as an element of perioperative pharmacotherapy in oncologic patients, increase the risk of tumor recurrence and affect further prognosis were presented. The actual publications suggest that there are multifactorial, complex mechanisms underlying the immunological impact and carcinogenesis promotion of opioids and that the intensity varies depending on the type of opioid. There are also questions about the immunosuppressive effects among patients receiving opioids in the treatment of chronic noncancer pain. The aim of the review article is to present information about the action of opioids on the immune system in carcinogenic settings and to define the clinical usefulness of this pharmacological phenomenon.


Subject(s)
Humans , Male , Female , Chronic Pain/drug therapy , Carcinogenesis , Analgesics, Opioid/adverse effects , Pituitary-Adrenal System/drug effects , Retrospective Studies , Drug Tolerance , Analgesics, Opioid/therapeutic use , Hypothalamo-Hypophyseal System/drug effects , Opioid-Related Disorders
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