TFAP2C increases cell proliferation by downregulating GADD45B and PMAIP1 in non-small cell lung cancer cells

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes of death in the world. NSCLC diagnosed at an early stage can be highly curable with a positive prognosis, but biomarker limitations make it difficult to diagnose lung cancer at an early stage. To identify biomarkers for lung cancer development, we previously focused on the oncogenic roles of transcription factor TFAP2C in lung cancers and revealed the molecular mechanism of several oncogenes in lung tumorigenesis based on TFAP2C-related microarray analysis. RESULTS: In this study, we analyzed microarray data to identify tumor suppressor genes and nine genes downregulated by TFAP2C were screened. Among the nine genes, we focused on growth arrest and DNA-damage-inducible beta (GADD45B) and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1) as representative TFAP2C-regulated tumor suppressor genes. It was observed that overexpressed TFAP2C resulted in inhibition of GADD45B and PMAIP1 expressions at both the mRNA and protein levels in NSCLC cells. In addition, downregulation of GADD45B and PMAIP1 by TFAP2C promoted cell proliferation and cell motility, which are closely associated with NSCLC tumorigenesis. CONCLUSION: This study indicates that GADD45B and PMAIP1 could be promising tumor suppressors for NSCLC and might be useful as prognostic markers for use in NSCLC therapy.

Foreign Bodies in the Ear, Nose and Throat: An Experience in a Tertiary Care Hospital in Central Nepal

Introduction A foreign body (FB) is an object or substance foreign to the location where it is found. FBs in the ear, nose, and throat are a common problem frequently encountered in both children and adults. Objective To analyze FBs in terms of type, site, age, and gender distribution and method of removal. Methods A retrospective study was performed in a tertiary care hospital in the central part of Nepal. The study period was from June 2013 to May 2014. The information was obtained from hospital record books. Results A total of 134 patients had FBs in the ear, nose, or throat; 94 were males and 40 were females. Of the 134 patients, 70 (52.23% ) had FB in the ear, 28 (20.89% ) in the nose, and 36 (26.86% ) in the throat. The FB was animate (living) in 28 (40% ) patients with FB in the ear and 1 (3.5% ) patient with FB in the nose, but the FB was inanimate (nonliving) in any patient with FB in the throat, in 42 (60% ) patients with FB in the ear FB, and in 27 (96.4% ) patients with FB of the nose. The FB was removed with or without local anaesthesia (LA) in 98 (73.13% ) patients, and only 36 patients (26.86% ) required general anaesthesia (GA). The most common age group affected was <10 years. Conclusion FBs in the ear and nose were found more frequently in children, and the throat was the most common site of FB in adults and elderly people. Most of the FBs can be easily removed in emergency room or outpatient department. .

Sheep gastrointestinal helminthiasis in the Sertão region of Paraíba State, Northeastern Brazil: prevalence and risk factors / Helmintoses gastrintestinais de ovinos no Sertão do Estado da Paraíba, Nordeste do Brasil: prevalência e fatores de riscos

In this study, we aimed to establish the prevalence and risk factors relating to gastrointestinal helminthiasis, and to characterize the sanitary management practiced among sheep herds in the Sertão region of the state of Paraíba, northeastern Brazil, based on factors that condition the ways of controlling these parasites in these herds. The research was carried out between April and July 2012. We visited 54 farms, where fecal and blood samples were individually collected from 465 animals. On each farm, a questionnaire was applied to gather information on variables relating to potential risk factors. The prevalence of sheep gastrointestinal helminthiasis in the region was 75.9%. At least one animal tested positive for this helminthiasis on 53 (98.1%) of the 54 farms evaluated. The eggs per gram of feces (EPG) analysis showed the following infection burdens: 51.8% with mild infection, 27.1% moderate infection, 9.9% heavy infection and 11.2% fatal infection. Among the sheep farms visited, anthelmintics were used on 81.5% (p <0.05). The most relevant risk factor in this study was the farm area, because it defines the area available for grazing animals. Properties with many animals and little pasture area, which are the most abundant type in the Sertão region of Paraíba, tend to have high prevalence of gastrointestinal helminthiasis, because the animals are more prone to reinfection. The Sertão region of Paraíba presents high prevalence of gastrointestinal helminthiasis among sheep, and the farm area is the most relevant risk factor for the development of these parasites.

Objetivou-se determinar a prevalência e os fatores de risco para as helmintoses gastrintestinais, caracterizando o manejo sanitário sob fatores condicionantes das formas de controle dessas parasitoses em rebanhos de ovinos da região do Sertão da Paraíba. A pesquisa foi desenvolvida no período de abril a julho de 2012. Foram visitadas propriedades, utilizando-se 465 animais, sendo coletadas individualmente amostras de fezes e sangue durante as visitas. Em cada propriedade, foi aplicado questionário para a coleta de informações acerca de variáveis que atuariam como possíveis fatores de risco. Observou-se que a prevalência das helmintoses gastrintestinais de ovinos na região do Sertão da Paraíba foi de 75,9%. Pelo menos um animal foi positivo para essas helmintoses, em 53 (98,1%) das 54 propriedades avaliadas. A análise de OPG (Ovos Por Gramas de Fezes) demonstrou que 51,8% dos animais apresentaram infecção leve, 27,1% infecção moderada, 9,9% infecção pesada e 11,2% infecção fatal. A utilização de anti-helmínticos ocorreu em 81,5% das propriedades (p <0,05). O fator de risco mais relevante neste estudo foi a área da propriedade, porque delimita a área de pastejo do animal. Propriedades com muitos animais e pouca área de pastejo, que são as mais abundantes no Sertão da Paraíba, tendem a apresentar alta prevalência de helmintoses gastrintestinais, pois os animais estão mais propensos à reinfecção. A região do Sertão da Paraíba apresenta uma elevada prevalência de helmintoses gastrintestinais em ovinos, e a área das propriedades é o fator de risco mais relevante para o desenvolvimento dessas parasitoses.

Perfil de metilación de genes supresores de tumores como factor pronóstico en pacientes con leucemia mieloide aguda / Promoter methylation profile in tumor suppressor genes as prognosis factor in patients with acute myeloid leukemia

Existe creciente evidencia que apoya la presencia de un perfil de metilación específico para Leucemia Mieloide Aguda (LMA). La metilación de los islotes CpG en las regiones promotoras de los genes supresores de tumores es un importante mecanismo de control epigenético y participa en el silenciamiento transcripcional. Esto puede contribuir a un nuevo entendimiento de la biología de la enfermedad y vislumbrar nuevas oportunidades terapéuticas. Identificar el perfil de metilación de las áreas promotoras de un grupo de genes supresores de tumores; (p15, p16, ESR1, IGSF4, SOCS1, RARB y DAPK), y relacionar el estatus de metilación gen especifica o combinada con diferentes parámetros clínico patológicos. Se utilizaron muestras de sangre o médula ósea obtenidas al momento del diagnóstico de 33 pacientes con LMA, infantil y del adulto, recolectadas entre los años 1997 y 2008 en el Hospital Hernán Henríquez de Temuco. Se evaluó la presencia de hipermetilación mediante una Reacción de Polimerasa en Cadena Metilación Específica (MSP), previa modificación con bisulfito de sodio. La frecuencia de metilación de los pacientes estudiados fue de 88 por ciento, 27 por ciento, 27 por ciento, 21 por ciento, 15 por ciento, 3 por ciento y 0 por ciento para ESR1, RARb, IGSF4, p15, SOCS1, DAPK, y P16, respectivamente. La hipermetilación de P15 y RARb presentó una asociación significativa para una menor supervivencia en forma individual (p=0,03 y p=0,02), y combinada (p=0,002). No se encontraron diferencias significativas entre metilación y los otros parámetros clínicos analizados. Los pacientes con LMA presentan hipermetilación de la región promotora en algunos genes supresores de tumores, afectando negativamente la supervivencia. Esto pudiese eventualmente contribuir al establecimiento de un patrón de metilación determinado con utilidad clínica.

There is growing evidence than acute myeloid leukemia presents a specific methylation profile. The Methylation of CpG islands within gene promoters is a major epigenetic transcriptional control mechanism and plays a critical role in the transcriptional silencing of tumor suppressor genes. This provides new insights into the biology of the disease and it may offer novel therapeutic opportunities. To identify the promoter methylation profile of tumor suppressor genes (p15, p16, ESR1, IGSF4, SOCS1, RARB y DAPK), and to relate the percentage of methylation with clinicopathological features, as age, gender, white cell count, disease classification and survival rates. Bone marrow and peripheral blood samples were collected at diagnosis from 33 patients with acute myeloid leukemia, infants and adult, between 1997 and 2008 from Hernán Henríquez Aravena Hospital, Temuco, Chile. Methylation in the promoter areas of each tumor suppressor gene was analyzed using the mehylation specific polymerase chain reaction (MSP) technique using sodium bisulfite modification. The frequency of hypermethylation among the patient samples was 88 percent, 27 percent, 27 percent, 21 percent, 15 percent, 3 percent and 0 percent for ESR1, RARb, IGSF4, p15, SOCS1, DAPK, and P16 for each one. Methylation was significantly associated with an inferior overall survival (p=0.03 and p=0.02). When both genes are used, inferior survival is even more significant (p=0.002). There is no significant correlation between methylation and clinicopathological features.Patients with AML have hipermetilation at the promoter region of some tumor supressor genes, with a negative effect in the overall survival. This could eventually become part of establishing a characteristical methilation pattern with clinical utility.

Hypomethylation of tumor suppressor genes in odontogenic myxoma

Odontogenic myxoma (OM) is an ectomesenchymal benign odontogenic tumor characterized by spindle or stellate-shaped cells embedded in an abundant myxoid or mucoid extracellular matrix. DNA methylation is characterized by the addition of methyl groups in cytosines within CpG islands in the promoter gene. DNA methylation can decrease the expression of tumor suppressor genes and contribute to the development of neoplastic lesions. The aim of study was to evaluate the methylation pattern of the tumor suppressor genes P16 (CDKN2A), P21 (CDKN1A), P27 (CDKN1B), P53 (TP53) and RB1 in OM and dental pulp. Methylation was evaluated using methylation-specific polymerase chain reaction (PCR). The transcription was studied in some cases by using reverse transcription quantitative PCR. A higher frequency of unmethylated P27, P53, and RB1 samples was observed in the OM when compared with the dental pulp. OM expressed mRNA of all the genes evaluated. Considering all the samples together, the expression of Rb was higher in the unmethylated samples compared with the partially methylated samples. This investigation revealed hypomethylation of the genes P27, P53, and RB1 in OM. In addition, methylation of tumor suppressor genes was found to be an usual event in normal dental pulp.

O mixoma odontogênico (MO) é um tumor odontogênico benigno de origem mesenquimal caracterizado pela presença de células fusiformes ou estreladas dispostas em abundante matriz extracelular mucóide. A metilação do DNA é caracterizada pela adição de grupos metil em citosinas constituintes de ilhas CpG na região promotora do gene. A metilação pode diminuir a expressão de genes supressores de tumor e contribuir para o desenvolvimento de lesões neoplásicas. O objetivo deste trabalho foi avaliar o padrão de metilação nos genes P16 (CDKN2A), P21 (CDKN1A), P27 (CDKN1B), P53 (TP53), RB1 nos MO e na polpa dental. A metilação foi avaliada pela reação em cadeia da polimerase específica para a metilação. A transcrição dos genes foi estudada em alguns casos pela reação da transcriptase reversa (PCR quantitativa). Uma maior frequência de amostras não metiladas para os genes P27, P53 e RB1 foi observada nos MO quando comparados à polpa dental. Os MO expressaram RNAm de todos os genes avaliados. Considerando todas as amostras juntas, a expressão de Rb foi maior em amostras não metiladas comparadas as amostras parcialmente metiladas. Esta investigação mostrou a hipometilação dos genes P27, P53 e RB1 nos MO. Adicionalmente, a metilação nos genes supressores de tumor é um evento frequente em polpa dental normal.

Aspectos moleculares da tumorigênese hipofisária: [revisão] / Molecular aspects of pituitary tumorigenesis: [review]

Os tumores hipofisários, adenomas em sua quase totalidade, são de ocorrência freqüente, representando 10 por cento a 15 por cento de todas as neoplasias intracranianas. Estas lesões são classificadas em microadenomas (< 10 mm) ou macroadenomas (> 10 mm) e como secretoras ou quiescentes (não-funcionantes). Estes tumores são capazes de secretar, de maneira autônoma, os hormônios adenohipofisários, como o hormônio de crescimento (GH), a prolactina (PRL), o hormônio adrenocorticotrófico (ACTH), o hormônio tireotrófico (TSH), o hormônio folículo estimulante (FSH) e o hormônio luteinizante (LH). A ocorrência de metástase, caracterizando um carcinoma hipofisário, é bastante rara, mas são relativamente comuns tumores de comportamento agressivo que exibem sinais de invasão local. Embora a sua patogênese ainda não seja plenamente caracterizada, muitos mecanismos moleculares envolvidos na tumorigênese hipofisária já foram desvendados. Nesta revisão, serão descritos avanços consideráveis realizados na última década relativos à compreensão dos fatores envolvidos na progressão tumoral, incluindo a participação de oncogenes, supressores tumorais e fatores de crescimento.

Pituitary tumors, almost invariably adenomas, are of frequent occurrence, accounting for 10 percent to 15 percent of all the intracranial neoplasm. They are classified as microadenomas (< 10 mm) or macroadenomas (> 10 mm) and as secreting or clinically non-secreting (or not functioning) adenomas. These tumors are autonomously capable to release pituitary hormones such as the growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone (ACTH), thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH) and luteinizing hormone (LH). The occurrence of metastases, characterizing a pituitary carcinoma, is exceedingly rare. However tumors with aggressive behavior, leading to local invasion, are relatively common. Although the pathogenesis of pituitary tumors is fully characterized, many molecular mechanisms of pituitary tumorigenesis had already been revealed. This review intents to describe advances in the understanding of the involved advances that have been made in the last decade concerning pituitary tumors progression, including the participation of oncogenes, tumor suppressor genes and growth factors.

Genética, biologia molecular e carcinogênese mamária / Genetics, molecular biology and mammary carcinogenesis

Neste artigo são apresentados conceitos atuais sobre a carcinogênese mamária, enfocando aspectos de genética e de biologia molecular. Sabe-se que a carcinogênese pode ser subdividida em três fases: iniciação, promoção e progressão. A iniciação decorre de lesão genética em uma única célula-tronco, quase sempre localizada em lóbulo indiferenciado (tipo I). A alteração genética fundamental é a inativação de genes supressores (esporádica ou hereditária) ou a ativação de proto-oncogenes. A promoção é basicamente hormonal, destacando-se o papel dos esteróides sexuais, que atuam mediante interação com proteínas receptoras intranucleares. Na fase de progressão, ocorre a invasão da membrana basal e do estroma e embolização linfática, após perda no processo de adesão entre as células em conseqüência de ação de enzimas proteolíticas.

Current concepts on mammary carcinogenesis focusing genetics and molecular biology are presented. The carcinogenic process can be divided in 3 phases: initiation, promotion and progression. Initiation occurs in only one stem cell located in undifferentiated lobules (type I) and is caused by a genetic damage. The main genetic alteration is suppressor gene inactivation (sporadic or hereditary) or proto-oncogene activation. Promotion is basically due to steroid hormones action which interacts with intra-nuclear receptor proteins. After loosing adhesion malignant cells produce proteolytic enzymes, invade basal membrane and stroma and can embolyze through lymphatic channels.

Molecular mechanisms of pancreatic cancer.

Pancreatic cancer is a deadly disease with no effective therapy short of surgical resection. Unfortunately, only a minority of patients are candidates for potential curative surgery as the tumor spreads early to extrapancreatic sites. Patients with metastatic pancreatic cancer survive less than 1 year following diagnosis. The current challenge for both clinicians and scientists is to translate the growing body of knowledge of the molecular basis of this disease into effective strategies for early diagnosis and systematic treatment. Molecular studies of pancreatic cancer have revealed that this cancer is associated with several genetic mutations. Although our knowledge of the molecular alterations in pancreatic cancer has grown significantly, there is still much to learn. It is clear that oncogenes, tumor suppressor genes, growth factors and DNA mismatch repair genes all play a role in pancreatic tumorigenesis. However, a better understanding of the relative contribution of each of these molecular alterations is necessary and will aid the development of more effective diagnostic and therapeutic strategies to deal with this deadly and aggressive cancer.

Bases moleculares dos adenomas hipofisários com ênfase nos somatotropinomas / Molecular basis of pituitary adenomas with emphasis on somatotropinomas

Esta revisão descreve as bases moleculares dos adenomas hipofisários com ênfase nos tumores secretores de GH (somatotropinomas). São discutidos os papéis de genes de supressão tumoral (como RB1, MEN-1) e de oncogenes (como gsp, PTTG) na iniciação e progressão destes tumores. A caracterização destes marcadores moleculares pode ajudar na compreensão do comportamento tumoral, auxiliando a conduta terapêutica. Entretanto, apesar dos recentes avanços, ainda não é totalmente conhecida a seqüência de alterações genéticas envolvidas na patogênese destes adenomas.

As alteraçöes gênicas e o desenvolvimento do câncer bucal / Gene mutations and the development of oral cancer

A etiologia do câncer oral envolve múltiplos fatores ambientais e genéticos. Neste artigo, apresentamos uma revisäo sobre os principais fatores etiológicos e, especialmente, sobre os principais genes envolvidos na gênese do câncer bucal

Genes oncosupresores: nuevas perspectivas para la investigación clínica en cáncer / Tumor suppressor genes: new perspectives for clinical investigations in cancer

La tumorigénesis comprende una serie de eventos genéticos específicos que ocurren en una célula y en sus descendientes clonales. El desarrollo de la biologia molecular durante la última década, permitió distribuir estos eventos dentro de dos categorías: la activación de protooncogenes y la inactivación de genes oncosupresores. Los genes oncosupresores son genes cuya inactivación es requerida para la transformación maligna de una célula. La pérdida de los genes oncosupresores juega un importante papel en el desarrollo de los tumores humanos. Estudios en hibridos celulares somáticos han demonstrado que la supresión tumorigénica ocurre en las células neoplásicas que reciben cromosomas humanos normales mediante fusión celular. Estos experimentos han demostrado que la tumorigénesis es un carácter fenotipicamente recessivo, controlado por cromosomas específicos. Ciertos tipos de genes oncosupresores, p. ej. p53 y RB1, están implicados en una gran variedad de neoplasias, mientras otros, p. ej., el gen DCC, están restingidos a un solo tipo de tumores. La detección de mutaciones germinales en los genes oncosupresores permitirá la identificación de los individuos con alto riesgo de desarrollar neoplasias

Genes Supresores de Tumores / Tumor Suppressor Genes

La inactivación de genes supresores de tumores ha sido asociada al desarrollo de cáncer en el hombre. Normalmente la regulación de la proliferación celular depende del balance entre señales que estimulan y señales que inhiben el crecimiento. Los genes supresores de tumores intervienen en el control negativo de la proliferación celular. Así la pérdida de la función de estos genes por mutaciones o interacciones con oncogenes virales es necesaria para el desarrollo de distintos tipos e tumores. El primer gen supresor de tumores aislado y caracterizado es el gen que predispone al retinoblastoma. Mutaciones en las dos copias de estos gens llevan a la aparición del retinoblastoma. Recientemente otros genes supresores de tumores han sido identificados. El estudio de estos genes es crucial para entender el proceso de oncogénesis y poder mejorar las terapias actuales.

Interacción del Virus del Papiloma Humano con genes supresores de Tumors / Interaction of the CPH with Tumor Suppressor genes

Los virus del papiloma humano de tipo 16 y 18 está asociados al desarrollo de cáncer ano-genital. La actividad transformante de estos virus depende de la expresión de los oncogenes virales E6 y E7. Estos dos genes son necesarios y suficientes para la transformación de ketatinocitos humanos. Esta actividad transformante involucra la interacción de estos oncogenes con genes supresores de tumores. El oncogen E7 se une al gen supresor de tumors retinoblastoma (Rb) impidiendo que actúe en forma normal. Por otro lado; el oncogen E6 se asocia al gen supresores de tumores p53 estimulando su degradación. De esta forma los oncogens virales al inactivar funcionalmente genes que controlan negativamente proliferación celular conducen a la transformación.