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Braz. j. med. biol. res ; 54(5): e10637, 2021. tab, graf
Article in English | LILACS | ID: biblio-1153548


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.

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
Braz. j. otorhinolaryngol. (Impr.) ; 82(6): 687-694, Oct.-Dec. 2016. tab, graf
Article in English | LILACS | ID: biblio-828255


Abstract Introduction: A key step of cancer development is the progressive accumulation of genomic changes resulting in disruption of several biological mechanisms. Carcinoma ex-pleomorphic adenoma (CXPA) is an aggressive neoplasm that arises from a pleomorphic adenoma. CXPA derived from a recurrent PA (RPA) has been rarely reported, and the genomic changes associated with these tumors have not yet been studied. Objective: We analyzed CXPA from RPAs and RPAs without malignant transformation using array-comparative genomic hybridization (array-CGH) to identify somatic copy number alterations and affected genes. Methods: DNA samples extracted from FFPE tumors were submitted to array-CGH investigation, and data was analyzed by Nexus Copy Number Discovery Edition v.7. Results: No somatic copy number alterations were found in RPAs without malignant transformation. As for CXPA from RPA, although genomic profiles were unique for each case, we detected some chromosomal regions that appear to be preferentially affected by copy number alterations. The first case of CXPA-RPA (frankly invasive myoepithelial carcinoma) showed copy number alterations affecting 1p36.33p13, 5p and chromosomes 3 and 8. The second case of CXPA-RPA (frankly invasive epithelial-myoepithelial carcinoma) showed several alterations at chromosomes 3, 8, and 16, with two amplifications at 8p12p11.21 and 12q14.3q21.2. The third case of CXPA-RPA (minimally invasive epithelial-myoepithelial carcinoma) exhibited amplifications at 12q13.3q14.1, 12q14.3, and 12q15. Conclusion: The occurrence of gains at chromosomes 3 and 8 and genomic amplifications at 8p and 12q, mainly those encompassing the HMGA2, MDM2, WIF1, WHSC1L1, LIRG3, CDK4 in CXAP from RPA can be a significant promotional factor in malignant transformation.

Resumo Introdução: Uma etapa fundamental do desenvolvimento do câncer é o acúmulo progressivo de alterações genômicas, resultando na ruptura de vários mecanismos biológicos. Carcinoma ex-adenoma pleomórfico (CXAP) é uma neoplasia agressiva que surge a partir de um adenoma pleomórfico. O CXAP derivado de um AP recorrente (APR) foi raramente relatado e, até o momento, as alterações genômicas associadas a esses tumores não foram estudados. Objetivo: Avaliar as diferenças entre os CXAPs decorrentes de APRs e os APRs sem transformações malignas usando hibridização genômica comparativa em microarrays (array Comparative Genomic Hibridization - aCGH) a fim de identificar alterações no número de cópias somáticas e os genes afetados. Método: Amostras de DNA extraídas de tumores provenientes de tecido emblocado em parafina foram submetidos à investigação com a técnica aCGH, e os dados foram analisados com o Nexus Copy Number Discovery Edition v.7. Resultados: Não observamos alterações no numero de cópias somáticas nos APRs sem transformação maligna. Quanto ao CXAP de APR, embora os perfis genômicos sejam exclusivos para cada caso, detectamos algumas regiões cromossômicas que pareciam ser preferencialmente afetadas por alterações no número de cópias. O primeiro caso de CXAP-APR (carcinoma mioepitelial francamente invasivo) apresentou alterações no numero de cópias afetando 1p36.33p13, 5p e cromossomos 3 e 8. O segundo caso de CXAP-APR (carcinoma epitelialmioepitelial francamente invasivo) apresentou várias alterações nos cromossomos 3, 8 e 16, com duas amplificações em 8p12p11.21 e 12q14.3q21.2. O terceiro caso de CXAP-APR (carcinoma epitelial-mioepitelial minimamente invasivo) apresentou amplificações em 12q13.3q14.1, 12q14.3, e 12q15. Conclusão: A ocorrência de ganhos de cromossomos 3 e 8, e as amplificações genômicas em 8p e 12q, principalmente aquelas que englobam os HMGA2, MDM2, WIF1, WHSC1L1, RG3, CDK4 no CXAP decorrente de APR podem ser fatores promocionais significativos para a transformação maligna.

Humans , Male , Female , Adult , Aged , Salivary Gland Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Adenoma, Pleomorphic/genetics , Salivary Gland Neoplasms/pathology , Cell Transformation, Neoplastic/pathology , Adenoma, Pleomorphic/pathology , Neoplasm Recurrence, Local
Arch. argent. pediatr ; 113(5): 390-396, oct. 2015. tab
Article in Spanish | LILACS | ID: lil-757059


Introducción. La presencia de infecciones de transmisión sexual (ITS) en pacientes con sospecha de abuso sexual es poco frecuente en pediatría. Objetivos. Determinar la prevalencia de hallazgos anogenitales y su relación con la presencia de ITS en niñas referidas por sospecha de abuso sexual infantil. Material y métodos. Estudio retrospectivo realizado entre el 1 de enero de 2003 y el 31 de diciembre de 2013. Se analizaron los hallazgos físicos y la detección de ITS en niñas con sospecha de abuso sexual infantil. Resultados. Se incluyeron 1034 pacientes. La mediana de edad fue 7,9 años. Los hallazgos anogenitales correspondieron a clase I (normal):38,4%; clase II (inespecífico):38,1%; clase III (específico):19,9%; y clase IV (certeza):3,6%. Se registraron ITS en 42 pacientes (4,1%). Se relacionaron las ITS con las clases de hallazgos físicos: 10 (clase II: 9; clase III: 1) Neisseria gonorrhoeae, 17 (clase I: 2; clase II: 8; clase III: 7) Chlamydia trachomatis, 15 (clase I: 2; clase II: 10; clase III: 3) Trichomonas vaginalis. Se hallaron diferencias estadísticamente significativas para Trichomonas vaginalis (p= 0,01) y Neisseria gonorrhoeae (p < 0,0001), y predominaron signos clínicos inespecíficos. Chlamydia trachomatis (p= 0,03) presentó similares registros en hallazgos inespecíficos como específicos. Conclusiones. En la mayoría de los casos de niñas con sospecha de abuso sexual infantil, los hallazgos anogenitales son normales o inespecíficos. La prevalencia de ITS en estas niñas es baja. Trichomonas vaginalis y Neisseria gonorrhoeae se relacionaron con hallazgos inespecíficos, y Chlamydia trachomatis, tanto con hallazgos específicos como inespecíficos.

Introduction. The presence of sexually transmitted infections (STIs) in patients with suspected sexual abuse is uncommon in the field of pediatrics. Objectives. To establish the prevalence of anogenital findings and their relation to the presence of STIs in girls referred for suspected child sexual abuse. Material and Methods. Retrospective study conducted between January 1st, 2003 and December 31st, 2013. Physical findings and detection of STIs in girls with suspected child sexual abuse were analyzed. Results. One thousand thirty-four patients were included. Their median age was 7.9 years old. Anogenital findings were classified as class I (normal):38.4%, class II (nonspecific):38.1%, class III (specific):19.9% and class IV (definitive):3.6%. STIs were observed in 42 patients (4.1%). A relation was established between STIs and the classification of physical findings: 10 (class II: 9; class III: 1) Neisseria gonorrhoeae, 17 (class I: 2; class II: 8; class III: 7) Chlamydia trachomatis, 15 (class I: 2; class II: 10; class III: 3) Trichomonas vaginalis. Statistically significant differences for Trichomonas vaginalis (p= 0.01) and Neisseria gonorrhoeae (p < 0.0001) were observed, with predominance of nonspecific clinical signs. Both nonspecific and specific findings were similarly observed for Chlamydia trachomatis (p= 0.03). Conclusions. Most cases of girls with suspected child sexual abuse had normal or nonspecific anogenital findings. The prevalence of STIs in these girls is low. Trichomonas vaginalis and Neisseria gonorrhoeae were related to nonspecific findings, while both nonspecific and specific findings were observed for Chlamydia trachomatis.

Animals , Humans , Carcinoma, Hepatocellular/metabolism , Cell Transformation, Neoplastic/metabolism , Liver Neoplasms/metabolism , Signal Transduction/drug effects , TNF-Related Apoptosis-Inducing Ligand/pharmacology , Apoptosis , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Survival , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Cell Transformation, Neoplastic/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , TNF-Related Apoptosis-Inducing Ligand/therapeutic use
Einstein (Säo Paulo) ; 13(2): 330-333, Apr-Jun/2015. graf
Article in English | LILACS | ID: lil-751422


ABSTRACT Decision-making is fundamental when making diagnosis or choosing treatment. The broad dissemination of computed systems and databases allows systematization of part of decisions through artificial intelligence. In this text, we present basic use of probabilistic graphic models as tools to analyze causality in health conditions. This method has been used to make diagnosis of Alzheimer´s disease, sleep apnea and heart diseases.

RESUMO A tomada de decisões é um aspecto fundamental na conduta de um diagnóstico ou tratamento. A ampla difusão dos sistemas computacionais e dos bancos de dados permite sistematizar, por meio do uso da inteligência artificial, parte dessa tomada de decisão. Neste texto, é apresentada, de modo básico, a possibilidade de uso dos modelos gráficos probabilísticos como ferramenta de análise na causalidade das condições de saúde. Essa metodologia vem sendo utilizada para diagnósticos da doença de Alzheimer, apneia do sono e doenças cardiológicas.

Animals , Mice , Cell Transformation, Neoplastic/genetics , Gastrointestinal Tract/pathology , Oncogenes , Gastrointestinal Neoplasms/pathology , Organ Culture Techniques
Article in English | WPRIM | ID: wpr-86395


Increasing evidence suggests that cancer stem cells (CSCs) are responsible for tumor initiation and maintenance. Additionally, it is becoming apparent that cyclooxygenase (COX) signaling is associated with canine mammary tumor development. The goals of the present study were to investigate COX-2 expression patterns and their effect on CSC-mediated tumor initiation in primary canine mammary tissues and tumorsphere models using immunohistochemistry. Patterns of COX-2, CD44, octamer-binding transcription factor (Oct)-3/4, and epidermal growth factor receptor (EGFR) expression were examined in malignant mammary tumor (MMT) samples and analyzed in terms of clinicopathological characteristics. COX-2 and Oct-3/4 expression was higher in MMTs compared to other histological samples with heterogeneous patterns. In MMTs, COX-2 expression correlated with tumor malignancy features. Significant associations between COX-2, CD44, and EGFR were observed in low-differentiated MMTs. Comparative analysis showed that the levels of COX-2, CD44, and Oct-3/4 expression varied significantly among TSs of three histological grades. Enhanced COX-2 staining was consistently observed in TSs. Similar levels of staining intensity were found for CD44 and Oct-3/4, but EGFR expression was weak. Our findings indicate the potential role of COX-2 in CSC-mediated tumor initiation, and suggest that COX-2 inhibition may help treat canine mammary tumors by targeting CSCs.

Animals , Hyaluronan Receptors/genetics , Biomarkers, Tumor/genetics , Cell Transformation, Neoplastic/genetics , Cyclooxygenase 2/genetics , Dog Diseases/genetics , Dogs , Female , Immunohistochemistry/veterinary , Mammary Neoplasms, Animal/genetics , Mammary Neoplasms, Experimental/genetics , Neoplastic Stem Cells/metabolism , Octamer Transcription Factor-3/genetics , ErbB Receptors/genetics , Retrospective Studies
Article in English | WPRIM | ID: wpr-220405


Basal-type breast cancers are among the most aggressive and deadly breast cancer subtypes, displaying a high metastatic ability associated with mesenchymal features. However, the molecular mechanisms underlying the maintenance of mesenchymal phenotypes of basal-type breast cancer cells remain obscure. Here, we report that KRAS is a critical regulator for the maintenance of mesenchymal features in basal-type breast cancer cells. KRAS is preferentially activated in basal-type breast cancer cells as compared with luminal type. By loss and gain of KRAS, we found that KRAS is necessary and sufficient for the maintenance of mesenchymal phenotypes and metastatic ability through SLUG expression. Taken together, this study demonstrates that KRAS is a critical regulator for the metastatic behavior associated with mesenchymal features of breast cancer cells, implicating a novel therapeutic target for basal-type breast cancer.

Animals , Breast Neoplasms/genetics , Cell Line, Tumor , Cell Transformation, Neoplastic/genetics , Disease Models, Animal , Epithelial-Mesenchymal Transition/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Heterografts , Humans , Neoplasm Invasiveness , Neoplasm Metastasis , Phenotype , Proto-Oncogene Proteins/genetics , Transcriptional Activation , ras Proteins/genetics
J. bras. nefrol ; 36(4): 519-528, Oct-Dec/2014. tab, graf
Article in Portuguese | LILACS | ID: lil-731156


Introdução: A doença renal crônica (DRC) e o tabagismo são problemas de saúde pública. Objetivo: Analisar o tabagismo como fator risco para a progressão da DRC. Métodos: Realizou-se uma revisão sistemática nas bases Medline, LILACS, SciELO, Google Acadêmico, e Embase com artigos publicados até fevereiro de 2013. Incluíram-se estudos: tipo coorte, ensaios clínicos e caso-controle. Realizados em seres humanos com idade ≥ 18 anos tendo tabagismo como fator de risco para progressão da DRC. Excluíram-se estudos que não referiam tabagismo e DRC no título ou tinham proposta de combate ao fumo. Resultados: Das 94 citações, 12 artigos foram selecionados. Destes, seis eram multicêntricos realizados em países desenvolvidos e quatro foram aleatorizados. Predominou o sexo masculino 51%-76%. Houve progressão associada ao tabagismo em 11 estudos. Identificou-se que o consumo ≥ 15 maços/ ano aumenta o risco de progressão da DRC. Conclusão: Tabagismo é fator de risco para progressão da DRC. .

Introduction: Chronic kidney disease (CKD) and smoking are public health problems. Objective: To assess smoking as a risk factor for progression of CKD. Methods: We conducted a systematic review in Medline, LILACS, SciELO, Google Scholar, Embase and with articles published until February/2013. Were included: cohort, clinical trials and case-control. Performed in humans, aged ≥ 18 years with smoking as a risk factor for progression of CKD. We excluded studies that reported no smoking and CKD in the title or had proposed to reduce smoking. Results: Among 94 citations, 12 articles were selected. Of these, six were multicenter conducted in developed countries, four were randomized. Males predominated 51-76%. There was associated with smoking progression in 11 studies. It was found that the consumption ≥ 15 packs/ year increases the risk of progression of CKD. Conclusion: Smoking is a risk factor for progression of CKD. .

Female , Humans , Breast Neoplasms/genetics , /genetics , Gene Amplification , Neoplasm Proteins , Phosphoprotein Phosphatases/genetics , Apoptosis/genetics , Breast Neoplasms/etiology , Cell Transformation, Neoplastic/genetics , Oncogenes/genetics
Rev. Inst. Med. Trop. Säo Paulo ; 55(5): 329-334, Sep-Oct/2013. tab, graf
Article in English | LILACS | ID: lil-685557


SUMMARY High-risk human papillomavirus (hr-HPV) infection is necessary but not sufficient for cervical cancer development. Recently, P16INK4A gene silencing through hypermethylation has been proposed as an important cofactor in cervical carcinogenesis due to its tumor suppressor function. We aimed to investigate P16INK4A methylation status in normal and neoplastic epithelia and evaluate an association with HPV infection and genotype. This cross-sectional study was performed with 141 cervical samples from patients attending Hospital Moncorvo Filho, Rio de Janeiro. HPV detection and genotyping were performed through PCR and P16INK4A methylation by nested-methylation specific PCR (MSP). HPV frequency was 62.4% (88/141). The most common HPV were HPV16 (37%), HPV18 (16.3%) and HPV33/45(15.2%). An upward trend was observed concerning P16INK4A methylation and lesion degree: normal epithelia (10.7%), low grade lesions (22.9%), high grade (57.1%) and carcinoma (93.1%) (p < 0.0001). A multivariate analysis was performed to evaluate an association between methylation, age, tobacco exposure, HPV infection and genotyping. A correlation was found concerning methylation with HPV infection (p < 0.0001), hr-HPV (p = 0.01), HSIL (p < 0.0007) and malignant lesions (p < 0.0001). Since viral infection and epigenetic alterations are related to cervical carcinoma, we suggest that P16INK4A methylation profile maybe thoroughly investigated as a biomarker to identify patients at risk of cancer. .

RESUMO É reconhecido que infecções por papilomavírus humanos de alto risco (HPV) são causa necessária, mas não suficiente para o desenvolvimento do câncer cervical. Recentemente, estudos de silenciamento gênico apontaram que a hipermetilação do gene p16INK4A é importante co-fator para a carcinogênese cervical, eliminando a função supressora de tumor da proteína p16 em lesões malignas. Entretanto poucos estudos avaliaram a relação da metilação com a progressão da doença. Nosso objetivo foi investigar o padrão de metilação do gene P16INK4A em diferentes graus de lesão cervical e sua associação com a infecção por diferentes tipos de HPV. Nosso estudo de corte transversal avaliou 141 amostras cervicais de pacientes atendidas no Hospital Moncorvo Filho, Rio de Janeiro. A detecção e tipagem do HPV foi realizada pela técnica de reação em cadeia da polimerase (PCR), e a metilação do gene P16INK4A pela PCR-metilação específica em formato nested (MSP). A frequência de HPV foi de 62,4% (88/141). O tipo mais prevalente foi o HPV16 (37%), seguido pelo HPV18 (16,3%) e HPV33/45 (15,2%). Curva ascendente foi observada quanto ao padrão de metilação do gene P16INK4A e o grau da lesão: a metilação foi identificada em somente 10,7% das amostras de epitélio normal, em 22,9% das lesões de baixo grau, em 57,1% das lesões de alto grau e em 93,1% dos carcinomas (p < 0,0001). Foram feitas análises univariada e multivariada a fim de correlacionar metilação, idade, exposição ao tabaco, infecção e genótipo de HPV. Foi encontrada correlação da metilação com a infecção pelo HPV (p < 0,0001), genótipos de alto risco (p = 0,01), ...

Adult , Aged , Aged, 80 and over , Female , Humans , Middle Aged , Young Adult , Cervical Intraepithelial Neoplasia/virology , /genetics , DNA Methylation/genetics , Papillomavirus Infections/genetics , Uterine Cervical Neoplasms/virology , Cross-Sectional Studies , Cell Transformation, Neoplastic/genetics , Cervical Intraepithelial Neoplasia/genetics , Cervical Intraepithelial Neoplasia/pathology , DNA, Viral/genetics , Genotype , Polymerase Chain Reaction , Papillomavirus Infections/pathology , Precancerous Conditions/genetics , Severity of Illness Index , Uterine Cervical Neoplasms/pathology
Article in English | WPRIM | ID: wpr-216010


Transformation of MDS into ALL during childhood is extremely rare. We report a rare case of an 8-yr-old girl who presented with refractory cytopenia of childhood (RCC) that transformed into ALL only 3 months after the diagnosis of childhood MDS. Although no cytogenetic abnormalities were observed in conventional karyotype and FISH analysis, we found several deletions on chromosomes 5q, 12q, 13q, and 22q. Partial homozygous deletion of the RB1 gene was observed on microarray analysis, with the bone marrow specimen diagnosed as ALL. This is the first case report of transformation of ALL from childhood MDS in Korea. We also compared the clinical, cytological, and cytogenetic features of 4 previously reported childhood MDS cases that transformed into ALL.

Bone Marrow Cells/pathology , Cell Transformation, Neoplastic/genetics , Child , Chromosome Aberrations , Female , Gene Deletion , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Myelodysplastic Syndromes/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Retinoblastoma Protein/genetics
Article in English | WPRIM | ID: wpr-81324


MicroRNAs (miRNAs) participate in diverse biological functions and carcinogenesis by inhibiting specific gene expression. We previously reported that suppression of adenine nucleotide translocase 2 (ANT2) by using the short hairpin RNA (shRNA) approach has an antitumor effect in several cancer cells. We here examined the influence of ANT2 on expression of miRNAs in hepatocellular carcinoma (HCC) to further elucidate the tumor-suppressive mechanism of ANT2 shRNA. We first carried out screening for miRNAs, whose expression is regulated by ANT2 suppression in the Hep3B HCC cell line using miRNA microarrays. Validation of candidate miRNAs was done by incorporating clinical samples, and their effects on the tumorigenesis of HCC were studied in vitro and in vivo. miR-636 was one of the miRNAs whose expression was highly upregulated by ANT2 suppression in miRNA microarray analysis, as confirmed by real-time reverse transcription-polymerase chain reaction. Notably, miR-636 was markedly downregulated in HCC tissues compared with matched non-neoplastic liver in clinical samples. Restoration of miR-636 in Hep3B cells led to significant reduction of cell proliferation and colony formation. miR-636 restoration resulted in a decreased level of Ras, one of the putative targets of miR-636, and inactivation of its signaling pathway. Moreover, tumorigenesis was efficiently suppressed by miR-636 in an in vivo tumor xenograft model of HCC. The data suggest that miR-636 might function as a tumor suppressor miRNA affecting HCC tumorigenesis via downregulation of Ras, and that ANT2 suppression by shRNA could exert an anticancer effect by restoring miR-636 expression in HCC.

Adenine Nucleotide Translocator 2/metabolism , Animals , Carcinoma, Hepatocellular/genetics , Cell Line, Tumor , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Gene Knockdown Techniques , Humans , Liver Neoplasms/genetics , Mice , Mice, Inbred BALB C , Mice, Nude , MicroRNAs/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , RNA, Small Interfering/metabolism , Signal Transduction/genetics , Transcription, Genetic , Tumor Stem Cell Assay , Up-Regulation/genetics , ras Proteins/genetics
Clinics ; 66(4): 523-528, 2011. ilus, tab
Article in English | SES-SP, LILACS, SES-SP | ID: lil-588898


OBJECTIVE: To compare the repetitive DNA patterns of human actinic keratoses and squamous cell carcinomas to determine the genetic alterations that are associated with malignant transformation. INTRODUCTION: Cancer cells are prone to genomic instability, which is often due to DNA polymerase slippage during the replication of repetitive DNA and to mutations in the DNA repair genes. The progression of benign actinic keratoses to malignant squamous cell carcinomas has been proposed by several authors. MATERIAL AND METHODS: Eight actinic keratoses and 24 squamous cell carcinomas (SCC), which were pair-matched to adjacent skin tissues and/or leucocytes, were studied. The presence of microsatellite instability (MSI) and the loss of heterozygosity (LOH) in chromosomes 6 and 9 were investigated using nine PCR primer pairs. Random Amplified Polymorphic DNA patterns were also evaluated using eight primers. RESULTS: MSI was detected in two (D6S251, D9S50) of the eight actinic keratosis patients. Among the 8 patients who had squamous cell carcinoma-I and provided informative results, a single patient exhibited two LOH (D6S251, D9S287) and two instances of MSI (D9S180, D9S280). Two LOH and one example of MSI (D6S251) were detected in three out of the 10 patients with squamous cell carcinoma-II. Among the four patients with squamous cell carcinoma-III, one patient displayed three MSIs (D6S251, D6S252, and D9S180) and another patient exhibited an MSI (D9S280). The altered random amplified polymorphic DNA ranged from 70 percent actinic keratoses, 76 percent squamous cell carcinoma-I, and 90 percent squamous cell carcinoma-II, to 100 percent squamous cell carcinoma-III. DISCUSSION: The increased levels of alterations in the microsatellites, particularly in D6S251, and the random amplified polymorphic DNA fingerprints were statistically significant in squamous cell carcinomas, compared with actinic keratoses. CONCLUSION: The overall alterations that were observed in the repetitive DNA of actinic keratoses and squamous cell carcinomas indicate the presence of a spectrum of malignant progression.

Humans , Carcinoma, Squamous Cell/genetics , DNA Primers/genetics , Keratosis, Actinic/genetics , Loss of Heterozygosity/genetics , Microsatellite Instability , Skin Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Chromosomes, Human, Pair 9 , DNA Fingerprinting , Disease Progression , Keratosis, Actinic/pathology , Random Amplified Polymorphic DNA Technique/methods
Invest. clín ; 51(4): 541-551, dic. 2010. ilus, tab
Article in English | LILACS | ID: lil-630911


Our objective was to determine the presence of chromosomal abnormalities in primary cultures of ovarian surface epithelial cells in women of different ages with no history of cancer. Throughout conventional cytogenetic techniques, we analyzed chromosome spreads of cultured ovarian epithelial cells from 10 donors who were 50 or more years old (B) and 16 controls between 20 and 49 years old (A), belonging to the mestizo population in Bogota DC, Colombia. Of the 26 cultures that were analyzed in passage 1, 61.5% had an abnormal chromosome complement (62.5% in A, and 60% in B). Abnormalities included polyploidies, endoduplications and monosomies. Deletions in chromosomes 3 and 11 were found in just one metaphase. None of the samples showed weaknesses or breakpoints. After transforming and applying the exact student’s t-test for variance heterogeneity, we found significant differences in the frequency of metaphases, that were higher in A than in B (p=0.05), and in the frequency of polyploidies, which were higher in B than in A (p=0.044). Through the application of the Mann-Whitney test, we determined that the frequency of endoduplications was higher in A than in B (p=0.126), without reaching significant differences. There were no significant differences in the frequency of monosomies. The level of significance was set at p £ 0.05. Taking into account that polyploidization is a marker of chromosomal instability and that the risk of cancer arising from the ovarian surface epithelium augments substantially after menopause, the increase in the frequency of age-associated polyploidies could be used as a predictor of ovarian cancer in women from an ethnically homogeneous population as the mestizo one in Bogota DC.

El objetivo del presente trabajo fue determinar la presencia de anormalidades cromosómicas en cultivos primarios de células del epitelio superficial ovárico en mujeres de diferentes edades, sin antecedentes de cáncer. Mediante técnicas de citogenética convencional fueron analizados extendidos de células epiteliales ováricas histológicamente normales, provenientes de cultivos primarios de 10 donantes de 50 o más años (B) y de 16 donantes entre 20 y 49 años que se utilizaron como grupo control (A), pertenecientes a la población mestiza de Bogotá DC, Colombia. De 26 cultivos examinados en pase 1, 61,5% presentó complemento cromosómico anormal, 62,5% en A y 60% en B. Las anomalías numéricas halladas, todas en mosaico, incluyeron poliploidías, endoduplicaciones y monosomías. En una única célula en metafase de un cultivo, se presentaron deleciones en los cromosomas 3 y 11. Ninguna muestra presentó fragilidades o roturas. Previa aplicación de transformaciones, con la prueba exacta t-student para varianzas heterogéneas, se encontraron diferencias significativas en la frecuencia de células con metafase normal, mayor en A que en B (p=0,05) y en la de poliploidías, mayor en B que en A (p=0,044). Con la prueba exacta de Mann-Whitney se determinó que la frecuencia de endoduplicaciones en A fue mayor que en B (p=0,126), sin alcanzar diferencias significativas y que no hubo diferencias significativas en la frecuencia de monosomías. El nivel de significación fue p £ 0,05. Si se tiene en cuenta que la poliploidización es un marcador de inestabilidad cromosómica y, que además, el riesgo de aparición de cáncer derivado del epitelio superficial del ovario aumenta sustancialmente después de la menopausia, el incremento en la frecuencia de poliploidías asociado con la edad podría ser utilizado como predictor de cáncer ovárico en mujeres de una población étnicamente homogénea como la población mestiza de Bogotá DC.

Aged , Female , Humans , Middle Aged , Chromosome Aberrations , Epithelial Cells/ultrastructure , Ovary/cytology , Age Factors , Aneuploidy , Cell Transformation, Neoplastic/genetics , Cells, Cultured/ultrastructure , Disease Susceptibility , Karyotyping , Metaphase , Mitotic Index , Ovarian Neoplasms/genetics , Postmenopause
Braz. j. med. biol. res ; 43(10): 920-930, Oct. 2010. ilus
Article in English | LILACS | ID: lil-561225


Maintenance of cell homeostasis and regulation of cell proliferation depend importantly on regulating the process of protein synthesis. Many disease states arise when disregulation of protein synthesis occurs. This review focuses on mechanisms of translational control and how disregulation results in cell malignancy. Most translational controls occur during the initiation phase of protein synthesis, with the initiation factors being the major target of regulation through their phosphorylation. In particular, the recruitment of mRNAs through the m7G-cap structure and the binding of the initiator methionyl-tRNAi are frequent targets. However, translation, especially of specific mRNAs, may also be regulated by sequestration into processing bodies or stress granules, by trans-acting proteins or by microRNAs. When the process of protein synthesis is hyper-activated, weak mRNAs are translated relatively more efficiently, leading to an imbalance of cellular proteins that promotes cell proliferation and malignant transformation. This occurs, for example, when the cap-binding protein, eIF4E, is overexpressed, or when the methionyl-tRNAi-binding factor, eIF2, is too active. In addition, enhanced activity of eIF3 contributes to oncogenesis. The importance of the translation initiation factors as regulators of protein synthesis and cell proliferation makes them potential therapeutic targets for the treatment of cancer.

Humans , Cell Transformation, Neoplastic/metabolism , /biosynthesis , Gene Expression Regulation, Neoplastic/genetics , Protein Biosynthesis/genetics , Cell Proliferation , Cell Transformation, Neoplastic/genetics , /genetics , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics
Dermatol. argent ; 16(5): 327-335, sep.-oct. 2010. graf, tab
Article in Spanish | LILACS | ID: lil-714922


El melanoma es un tumor que ha crecido en frecuencia y para el cual todavía no existe un tratamiento efectivo. En la génesis del melanoma participan factores externos, como la radiación ultravioleta (RUV), y factores genéticos. Si bien el estudio de los genes involucrados en el melanoma aun está en su inicio, se conocen en la actualidad múltiples mutaciones genéticas transmisibles que confieren a su portador mayor riesgo de desarrollar melanoma, tales como las del gen CDK-N2A, del receptor de la melanocortina 1 (MCR1) y las de los genes de la vía de las MAP kinasas, entre otras. Muchos de estos genes determinan la predisposición al melanoma familiar o al melanoma múltiple y aumentan la susceptibilidad a otros tumores no cutáneos. El conocimiento cada vez más exacto y complejo de la acción de cada gen en la génesis y en la progresión del melanoma permitirá en un futuro próximo la creación de tratamientos más eficaces y más específicos para cada paciente.

Cutaneous melanoma is an increasingly frequent tumor that, as yet,does not have a satisfactory treatment. Environmental risk factors such as ultraviolet radiation (UVR) and genetic factors as well, participate in its genesis. Although studies of the genes involved in melanoma are scarce, it is well known that multiple transmissible genetic mutations, such as CDKN2A gene, the melanocortin-receptor 1(MCR1) gene and the MAPK signaling pathway genes, among others,confer to their carrier greater risk of developing melanoma. Many of these genes determine the predisposition to familial or multiple melanoma and increase the susceptibility to noncutaneous tumors. The precise and more complex knowledge of the role of each gene in the genesis and progression of melanoma, will allow the development of more successful and specific treatments for each patient in thenear future.

Humans , Male , Female , Melanoma/diagnosis , Melanoma/genetics , Melanoma/pathology , Family , /genetics , /metabolism , Skin Neoplasms/diagnosis , Skin Neoplasms/genetics , Phosphorylation , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Cell Transformation, Neoplastic/genetics
Article in English | WPRIM | ID: wpr-98796


Alterations of genes are known to be critical for the induction of tumorigenesis, but the mechanism of ovarian carcinogenesis is little understood and remains to be elucidated. In this study, we investigated the roles of brca1, brca2 and p53 genes in the development of ovarian cancer using conditional knockout mice generated by a Cre-loxP recombinant system. Following the application of recombinant adenovirus expressing Cre in vitro, the proliferation of ovarian surface epithelium (OSE) was increased. For instance, a significant increase in cell growth was observed in OSE cells in vitro by conditional knockout isolated from the mice bearing concurrent floxed copies of brca1 and brca2/p53. However, the proliferative effect of the ovarian cells was not observed in concurrent brca1/brca2 or p53 knockout mice in vivo, indicating that we could not observe the direct evidence of the involvement of brca1, brca2, and p53 in ovarian carcinogenesis. Since morphological changes including tumor formation were not observed in mice bearing floxed copies of concurrent brca1/brca2 or p53, the inactivation of brca1/2 or p53 is not sufficient for the induction of tumor formation. Taken together, these results suggest that the deficiency of these genes may not be involved directly in the mechanism of ovarian carcinogenesis.

Animals , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Epithelium/pathology , Extracellular Matrix Proteins/genetics , Female , Gene Silencing , Mice , Mice, Knockout , Ovarian Neoplasms/genetics , Protein-Lysine 6-Oxidase/genetics , Tumor Cells, Cultured , Tumor Suppressor Protein p53/genetics
Saudi Medical Journal. 2009; 30 (11): 1381-1389
in English | IMEMR | ID: emr-102325


Cancer stem cell [CSC] hypothesis provides us with a new approach to the understanding of carcinogenesis, therapeutics, and prevention strategies. In recent years, the origin and biological characteristics of CSC were widely studied in solid tumors; it is astonishing to find out the delicate relevancy between CSC and committed progenitors evolved from embryonic stem cells [ESC] during organ development. In this review, we propose that some key molecular signal pathways during lung development are crucial for abnormal self-renewal and differentiation of lung cancer stem cell as well as try to elaborate the lung CSCs from the point view of ontogeny

Humans , Male , Female , Neoplastic Stem Cells/pathology , Cell Transformation, Neoplastic/genetics , Research Design , Cell Proliferation , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Cytogenetic Analysis , Signal Transduction
Cir. & cir ; 76(1): 87-93, ene.-feb. 2008. ilus, tab, graf
Article in Spanish | LILACS | ID: lil-568173


Breast cancer is classified based on clinical stage, cellular morphology and immunohistochemical analysis. More precise prognostic factors are necessary to aid with therapeutic decisions. Breast cancer subtypes that differ in their genetic expression and prognosis have been determined using cDNA microarrays. These findings confirm the differences between the phenotypes and provide new knowledge about the biology of breast cancer. Based on the presence or absence of expression of the estrogen receptor (ER), breast cancer is divided in two groups: ER+ and ER-. Genetic expression profile has identified two subtypes of the ER+ tumors: luminal A and luminal B. ER- tumors also include two subtypes, the HER2+ and the basal type. These subtypes differ in their biology and both demonstrate short disease-free periods after treatment and poorer outcome. This classification has shown the relationship between cDNA microarrays and clinical outcome of these tumors. This classification is proposed as a method of identifying those patients who will demonstrate better results with the different adjuvant modalities.

Humans , Female , Gene Expression Profiling , Breast Neoplasms/classification , DNA, Complementary/genetics , DNA, Neoplasm/genetics , Cell Division/genetics , Forecasting , Kaplan-Meier Estimate , Models, Biological , Mexico/epidemiology , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/genetics , Oligonucleotide Array Sequence Analysis , /analysis , Receptors, Estrogen/analysis , Receptors, Estrogen/genetics , Treatment Outcome , Cell Transformation, Neoplastic/genetics
An. acad. bras. ciênc ; 79(4): 593-616, Dec. 2007. ilus, tab
Article in English | LILACS | ID: lil-470035


The use of chemical compounds benefits society in a number of ways. Pesticides, for instance, enable foodstuffs to be produced in sufficient quantities to satisfy the needs of millions of people, a condition that has led to an increase in levels of life expectancy. Yet, at times, these benefits are offset by certain disadvantages, notably the toxic side effects of the chemical compounds used. Exposure to these compounds can have varying effects, ranging from instant death to a gradual process of chemical carcinogenesis. There are three stages involved in chemical carcinogenesis. These are defined as initiation, promotion and progression. Each of these stages is characterised by morphological and biochemical modifications and result from genetic and/or epigenetic alterations. These genetic modifications include: mutations in genes that control cell proliferation, cell death and DNA repair - i.e. mutations in proto-oncogenes and tumour suppressing genes. The epigenetic factors, also considered as being non-genetic in character, can also contribute to carcinogenesis via epigenetic mechanisms which silence gene expression. The control of responses to carcinogenesis through the application of several chemical, biochemical and biological techniques facilitates the identification of those basic mechanisms involved in neoplasic development. Experimental assays with laboratory animals, epidemiological studies and quick tests enable the identification of carcinogenic compounds, the dissection of many aspects of carcinogenesis, and the establishment of effective strategies to prevent the cancer which results from exposure to chemicals.

A sociedade obtém numerosos benefícios da utilização de compostos químicos. A aplicação dos pesticidas, por exemplo, permitiu obter alimento em quantidade suficiente para satisfazer as necessidades alimentares de milhões de pessoas, condição relacionada com o aumento da esperança de vida. Os benefícios estão, por vezes associados a desvantagens, os efeitos resultantes da exposição a compostos químicos enquadram-se entre a morte imediata e um longo processo de carcinogênese química. A carcinogênese química inclui três etapas definidas como iniciação, promoção e progressão. Cada uma delas caracteriza-se por transformações morfológicas e bioquímicas, e resulta de alterações genéticas e/ou epigenéticas. No grupo das alterações genéticas incluem-se mutações nos genes que controlam a proliferação celular, a morte celular e a reparação do DNA - i.e. mutações nos proto-oncogenes e genes supressores de tumor. Os fatores epigenéticos, também considerados como caracteres não genéticos, podem contribuir para a carcinogênese por mecanismos de silenciamento gênico. A utilização de diferentes metodologias possibilita o reconhecimento e a compreensão dos mecanismos básicos envolvidos no desenvolvimento do cancro. Ensaios experimentais comanimais de laboratório, estudos epidemiológicos e alguns testes rápidos permitem identificar compostos carcinogênicos, analisar os eventos envolvidos na carcinogênese e estabelecer estratégias para prevenir a exposição a estes agentes.

Animals , Humans , Carcinogens/toxicity , Cell Transformation, Neoplastic/chemically induced , Neoplasms/chemically induced , Carcinogens/classification , Cell Transformation, Neoplastic/genetics , Neoplasms/genetics , Risk Factors