O carcinoma epidermóide representa mais de 90% das neoplasias malignas de cabeça e de pescoço, apresentando taxas elevadas de morbi-mortalidade. Proteínas relacionadas à invasão e proliferação celular estão em evidência devido ao seu envolvimento na carcinogênese, a exemplo da vimentina, encontrada em células de origem mesodérmica. Sua presença em células epiteliais neoplásicas contribui na transição epitélio mesenquimal e está associada à tumorigênese, à invasão celular e à metástase. O propósito deste estudo foi analisar através de métodos qualitativos (imunofluorescência e imunoistoquímica) e quantitativos (Western Blot) a expressão da vimentina em linhagens celulares de carcinoma epidermóide de cabeça e de pescoço (CECP) e em uma linhagem de queratinócitos imortalizados (HaCat) submetidas ao cultivo tridimensional em Matrigel®. O grupo controle foi representado pelas mesmas linhagens cultivadas na ausência de Matrigel®. A Vimentina apresentou marcação citoplasmática em algumas células das linhagens estudadas, exceto na HaCat, com evidente diminuição da sua expressão quando submetida ao cultivo com Matrigel®. Esses resultados foram confirmados por Western Blot. A expressão da Vimentina em diferentes linhagens de CECP pode variar dependendo da linhagem analisada, da reação de suas células aos componentes da matriz extracelular e da técnica utilizada para avaliação da expressão da proteína. / Head and neck squamous cell carcinoma (HNSCC) represents more than 90% of all head and neck malignancies, causing more deaths than any other oral disease. Proteins related to cancer growth, invasion and metastasis are in evidence due to their involvement in carcinogens, such as vimentin. This protein is observed in mesenquimal cells, however, it is considered a common finding in cervix, breast and bladder tumours. Thus its presencence in epithelial neoplasic cells contributes to epithelial-mesenchymal transition associated with tumorigenesis and tumor progression. The aim of this study was to analyse through Western Blot, Immunohistochemistry and Immunofluorescence methods, the expression of Vimentin in three different HNSCC cell lines and HaCat cell line (immortalized keratinocytes) submitted to a 3D assay into Matrigel®. The control group was represented by the same cell lines, without any treatment. Results showed that Vimentin had citoplasmatic staining in some cell of lines studied, except for HaCat cells, with evident decrease in its expression when submitted to cultive into Matrigel®. These findings were confirmed by Western Blot. Taking these results together, we conclude that in squamous cell carcinoma, the Vimentin is related to the process of tumour invasion and metastasis. This fact was showed by the reduction of its expression after treatment with Matrigel®. Therefore, the expression of Vimentin in different cell lines of HNSCC may vary according to the stimulus and, fundamentally, the localization of the tumor and the individual characteristics of neoplasic cells.

Diversas alterações genéticas estão associadas à patogênese do carcinoma epidermoide (CE), neoplasia maligna mais comum de cabeça e pescoço. Algumas dessas alterações comprometem proteínas pertencentes à via de sinalização do Akt, envolvida em diferentes fenômenos celulares. Este trabalho teve como objetivo estudar a expressão da proteína pAkt em linhagens celulares de carcinomas epidermoides de cabeça e pescoço, de forma a verificar possíveis alterações na transcrição dessa molécula em células de CE tratadas com Curcumina. Foram utilizadas duas linhagens celulares de CE de cabeça e pescoço (FaDu e SCC9) e uma linhagem de queratinócitos normais (HaCat) divididas em dois grupos: a. Grupo controle não tratado; b. Células tratadas com Curcumina. A proliferação celular foi monitorada através do teste de viabilidade celular e a análise da expressão de proteína foi realizada através da técnica do Western Blotting que revelou supressão do pAkt na linhagem celular SCC9 nos tempos de 24 e 48 horas. Desta forma, conclui-se que a Curcumina na via do Akt em carcinomas epidermoides de cabeça e pescoço tem importante ação supressora do gene pAkt. / Several genetic alterations are associated with the pathogenesis of squamous cell carcinoma (SCC), the most common malignant neoplasm of the head and neck. Some of these changes compromise the proteins belonging to the Akt signaling pathway, involved in various cellular phenomena. The objective of this study to explores the expression of the pAkt protein in cell lines of the squamous cell carcinomas of the head and neck to verify possible changes in the transcription of this molecule in EC cells treated with curcumin. The study used two cell lines of EC head and neck (FaDu and SCC9) and a normal line of keratinocytes (HaCat), split into two groups: A. the controlled group, untreated; B. Cells treated with curcumin. The cell proliferation it was observed by cell viability test and analysis of protein expression performed through Western blotting technique revealed suppression of pAkt in SCC9 cell line at 24 and 48 hours. Thus, it is concluded that the Curcumin on the path of Akt in squamous cell carcinoma of the head and neck has a significant suppressive effect of gene Akt.

O câncer de cavidade oral é uma das neoplasias mais comuns no Brasil e no mundo, porém seu prognóstico ainda é incerto principalmente devido ao diagnóstico tardio e presença de metástases. A análise de fatores relacionados ao prognóstico dessa doença é de suma importância e, o receptor de quimiocina denominado CXCR4, está sendo relacionado a um pior prognóstico devido a maior capacidade de invasão das células que o expressam, em diversas neoplasias. Apesar dessa relação estar demonstrada em vários tipos de cânceres, com relação ao de cavidade oral pouco se sabe até o momento. Assim, objetivo desse trabalho foi analisar a expressão imuno-histoquímica do receptor de quimiocina CXCR4 em carcinomas epidermóides de cavidade oral, e relacioná-la com variáveis clínicas e histológicas. Foram obtidos 94 blocos de carcinomas epidermóides oriundos de instituições parceiras para obtenção de cortes histológicos convencionais, corados com hematoxilina e eosina (HE), e cortes de TMA (tissue microarray). Foi realizado imuno-histoquímica para anticorpo anti-CXCR4 (ab124824, ABCAM, EUA) e análise da marcação em lâminas de TMA utilizando o software Image J (versão 1.49u). A intensidade de marcação imuno-histoquímica foi correlacionada com dados clínicos (TNM, tabagismo, etilismo e sobrevida) e histopatológicos (diferenciação histológica, infiltrado inflamatório e infiltração vascular, linfática e perineural) dos pacientes. Dos casos analisados 74,4% exibiram uma marcação fortemente positiva para o CXCR4, enquanto que o epitélio não tumoral mostrou uma marcação negativa ou fracamente positiva (71,1%; p=0,011). Tumores classificados como \"bem diferenciados\" apresentaram marcação fortemente positiva para a proteína estudada (53,3%; p=0,049). Não houve associação entre a marcação imuno-histoquímica do CXCR4 com sobrevida global em 5 anos (?2= 0.3, p=0.565). Os resultados sugerem que a alta expressão dessa proteína não influencia no prognóstico e na sobrevida desses pacientes. / Oral cancer is one of the most common neoplasia in Brazil and the world. Mainly due to a late diagnosis and presence of metastases its prognosis is still uncertain. Finding biological markers related to the prognosis of this disease is of paramount importance. The chemokine receptor CXCR4 is being related to a worse prognosis in several neoplasms because cells expressing it acquire a greater capacity of invasion. Although this relationship is demonstrated in several types of cancers, in the oral cavity it is uncertain. The aim of this study was to analyze by immunohistochemistry the CXCR4 chemokine receptor expression in oral squamous cell carcinomas, and related to clinical and histological variables. Conventional histological sections stained with hematoxylin and eosin (HE) were acquired from 94 blocks of oral squamous cell carcinoma for histological analysis. TMA (tissue microarray) was assembled from these blocks for anti-CXCR4 immunohistochemistry (ab124824, ABCAM, USA). Staining analysis was performed using Image J software (version 1.49u). The immunohistochemical signal intensity was correlated with clinical (TNM, smoking, alcoholism and survival) and histopathological parameters (histological differentiation, inflammatory infiltration, vascular, lymphatic and perineural infiltration). From the cases studied 74.4% showed a strong positivity for CXCR4, and the non-tumoral epithelium was negative or weakly positive (71.1%; p = 0.011). Tumors histologically well differentiated were strongly positive for the protein studied (53.3%; p = 0.049). There was no association between CXCR4 signal and global survival in 5 years (?2= 0.3, p=0.565). These results suggest that a high expression of CXCR4 it is not related to prognosis and survival of patients of patients with oral squamous cell carcinoma.

Oncolytic viruses can be genetically modified to limit their replication in normal cells rendering them a cancer specific treatment. In addition, they can induce a 'danger signal' in the form of pathogen- and damage-associated molecular patterns leading to anti-tumour immunity. Furthermore, they can be armed with various immunomodulatory molecules to further enhance anti-tumour immunity. In this project I aim to exploit these qualities to develop a translatable cancer vaccine. Virus-infected cancer cells were injected subcutaneously in a prime/boost regimen. Dying cancer cells will release the required danger signal leading to dendritic cell activation and cross-presentation of tumour associated antigens to T cells to elicit an anti-tumour immune response. Our results in the murine pancreatic cancer model showed that vaccination with virusinfected DT6606 cells induced tumour specific immunity capable of protecting vaccinated animals against re-challenge with tumour cells. The highest level of interferon gamma production, a surrogate marker of anti-tumour immunity, was achieved when animals were primed with adenovirus-infected cells. There was no significant difference between various boost groups. To enhance the safety of the proposed protocol a secondary treatment was introduced to arrest the proliferation of tumour cells prior to injection. Our results confirmed that secondary treatment with mitomycin does not affect the induction of tumour specific immunity and it does not affect the release of pathogen-associated molecular patterns in the form of viral proteins and DNA. To test our vaccination regimen in head and neck squamous cell carcinoma (HNSCC) we develop a clinically relevant mouse model using SCC7, B4B8 and LY2 cells to replicate various clinical scenarios including locally advancing disease and post excision locoregional recurrence. Vaccinating mice with HNSCC cells pre-infected with our recently developed tumour-targeted triple-deleted adenovirus (AdTD) resulted in a cell-specific antitumour immune response. In addition, it resulted in an increase in effector memory T-cells of both CD4+ and CD8+ phenotypes. Efficacy studies showed our vaccination can significantly slow down the growth rate of tumours in locally advancing disease. This led to increase survival of the vaccinated mice although it did not reach statistical significance. To further enhance the efficacy of our vaccination regimen, we aimed to increase T cell trafficking to the tumour site. CCL25 is a gut homing chemokine. Priming T cells in the presence of CCL25 will lead to upregulation of the surface expression of α4β7 integrin. The latter is a ligand of MAdCAM-1, a cell adhesion molecule highly expressed in the gut and pancreatic tumours. The α4β7/MAdCAM-1 interaction results in preferential homing of activated T cells to these organs. We hypothesised that vaccinating mice with pancreatic tumour cells pre-infected with a CCL25-armed adenovirus will lead to increased T cell trafficking to pancreatic tumours leading to enhanced efficacy. Although we achieved encouraging results in our pilot experiment, we did not detect any significant increase in α4β7 expression once we added a secondary treatment to the vaccination protocol. Similarly, efficacy experiments in the pancreatic cancer transgenic KPC mice did not show any difference in survival between AdTD-CCL25 and the control virus although both groups showed a trend towards increased survival compared to naïve mice. In conclusion, Virus-infected cancer cell vaccine is a potentially promising immunotherapeutic strategy that can be combined with traditional cancer therapies to increase survival of HNSCC and pancreatic cancer patients.

The high incidence of gastrointestinal cancers in the general population and the presence of premalignant dysplastic precursor lesions in the gastrointestinal tract make the gastrointestinal tract an ideal environment to study cancer clonality and clonal expansion. Background: Intestinal metaplastic (IM) glands in the human stomach are clonal, contain multiple stem cells and spread by fission. This mechanism of gland fission causes field cancerisation. We hypothesised that gastric adenocarcinoma (GA) progresses through a series of genetic events arising from a founder mutation. A process analogous to niche succession may also take place in the normal oesophagus. We hypothesise that oesophageal squamous cell cancer occurs by a process of field cancerisation of the oesophagus. RHBDF2 has been identified as the gene responsible for tylosis with oesophageal carcinoma (TOC). We hypothesise that RHBDF2 germline gain of function mutations might be lost during tumour progression in TOC and this might affect iRhom2 localisation in the cell. Methods and results: A cohort of 23 patients with dysplasia and a cohort of 51 GA patients were screened for genes accounting for 75% of all somatic mutations previously reported in GA. Only 13% of dysplastic patients and 31.4% of GA patients had mutations. Three dysplastic patients and six GA patients were analysed by microdissection. Small gastric cancer foci in a cohort of hereditary diffuse gastric cancer (HDGC) patients (n=5) were also screened by laser-capture microdissection (LCM) for mutations in TP53. A cohort of 30 patients was screened for common mutations in OSCC and for RHBDF2 mutations. 36.36% of the patients presented mutations. Three patients with mutations were randomly selected and areas of oesophageal squamous cell dysplasia and OSCC were analysed by LCM. Three TOC patients were also analysed by LCM and immunohistochemistry was performed for iRhom2 and ADAM17. Conclusions: The usual mutational events established for GA development during the metaplasiadysplasia- carcinoma sequence (MCS) do not fit the results from either of our two LCM mutation studies in the human stomach. Dysplasia was shown to be clonal and GA demonstrates genetic heterogeneity through clonal evolution. Field cancerisation could not be detected in HDGC using TP53 as a clonal marker. The low incidence of OSCC patients with mutations implies that other genes may be involved in the premalignant pathway leading to OSCC. Oesophageal squamous cell dysplasia and OSCC demonstrate clonal expansion through tumour progression. RHBDF2 mutations do not occur in sporadic OSCC but germline RHBDF2 mutations can be lost during tumour progression in TOC patients with LOH in 17q. Overall, the somatic mutation theory of carcinogenesis seems to hold true for both the progression to GA and OSCC, as both carcinomas seem to evolve from a single mutated stem cell and acquire genetic heterogeneity as the tumours evolve.

Orientador: Ana Maria Pires Soubhia / Banca: Suzana Cantanhede Orsini Machado de Souza / Banca: Décio dos Santos Pinto Júnior / Resumo: A incidência mundial de câncer em jovens tem aumentado e estudos recentes mostram que o câncer de boca também segue esta tendência. O objetivo deste trabalho foi avaliar e comparar as características clínicas, histopatológicas e imunoistoquímicas entre pacientes jovens, com idade igual ou inferior a 40 anos, e pacientes idosos, com idade igual ou superior a 65 anos, diagnosticados com carcinoma espinocelular em língua. Foram selecionados 19 casos de pacientes jovens e 19 casos de pacientes idosos e coletados dados clínicos dos prontuários. A gradação histológica foi realizada utilizando os critérios de classificação de Bryne et al (1992), na região do fronte tumoral. Também foi analisada a expressão imunoistoquímica das proteínas Bcl-2, Cerb-b2 e Ki-67. Neste estudo foi observado maior número de carcinomas espinocelulares moderadamente e pobremente diferenciados no grupo de pacientes jovens enquanto que no grupo de idosos houve maior prevalência de carcinomas bem diferenciados. Houve também no grupo de pacientes jovens um aumento do infiltrado linfoplasmocitário. A expressão imunoistoquímica das proteínas Bcl-2, Cerb-b2 e Ki-67 não mostrou diferenças significantes no fronte tumoral entre pacientes jovens e idosos. Na amostra estudada, foram detectadas diferenças morfológicas entre o grupo de pacientes jovens e idosos, no entanto, estas diferenças não foram expressas de forma significativa na análise imunoistoquímica. / Abstract: The worldwide incidence of cancer in young is increasing and recent studies show that the oral cancer also follows this trend. The objective of this study was to evaluate and to compare the clinical, histopathological and immunohistochemical features between young patients, with 40 years old or less, and elderly patients, with 65 years old or a superior age, diagnosed with tongue squamous cell carcinoma. Nineteen cases of young patients and 19 cases of elderly patients were selected and clinical data were collected from medical records. The histological grading was carried out using the criteria of classification of Bryne et al (1992) in the tumoral front region. The immunohistochemical expression of the proteins Bcl-2, Cerb-b2 and Ki-67 was also analyzed. In the present study, the group of young patients presented a higher number of moderately and poor differentiated squamous cell carcinomas whereas the elderly group had a greater prevalence of well differentiated carcinomas. The group of young patients also showed an increase in the lympho-plasmacytic infiltration. The immunohistochemical expression of the proteins Bcl-2, Cerb-b2 and Ki-67 did not show significant differences in the tumoral front region between young and elderly patients. In the studied sample, morphological differences between the group of young and elderly patients were detected, however, these differences were not expressed in in the immunohistochemical analysis. / Mestre

Orientador: Janete Dias Almeida / Coorientador: Celina Faig Lima Carta / Banca: Emília Ângela Lo Schiavo Arisawa / Banca: Ana Lia Anbinder / Banca: Alberto José de Araújo / Banca: José Benedito Oliveira Amorim / Resumo: Os carcinógenos do tabaco estão relacionados a diversos tipos de câncer incluindo o carcinoma de células escamosas (CCE) bucal. Aliado ao álcool, o tabaco contribui para o desfecho desfavorável destes casos. A susceptibilidade individual ao câncer pode estar relacionada a expressão das enzimas que metabolizam tais carcinógenos. O objetivo deste trabalho é avaliar a expressão dos genes CYP1A1, CYP1B1, CYP2A6 e CYP2E1 no CCE bucal por meio de qPCR. Foram coletadas amostras de 32 indivíduos com CCE e de 15 controles submetidos a cirurgias bucais por lesões benignas. Foram constituídos quatro grupos: Grupo CCE fumante (n=26), Grupo CCE não fumante (n=6), Grupo controle fumante (n=9) e Grupo controle não fumante (n=6). O Teste de Fagerström para Dependência a Cigarros (TFDC) foi usado para avaliar a dependência nicotínica (DN) e AUDIT para avaliação do consumo de etílicos. Houve diminuição da expressão do gene CYP1B1 nos casos de CCE comparados aos controles. Foram encontradas diferenças estaticamente significativas de expressão gênica de CYP1B1 entre os Grupos CCE fumante e controle fumante (p=0,0018), Grupo CCE não fumante e controle não fumante (p=0,0079) e CCE fumante com CCE não fumante (p=0,0385) e entre os quatro grupos (p<0,0001). Houve diminuição da expressão do CYP2A6 no Grupo CCE fumante em relação ao Grupo controle, mas apenas um paciente do Grupo controle expressou este gene. Houve aumento da expressão de CYP2E1 entre os Grupos CCE fumante e controle fumante (p=0,0424... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Tobacco carcinogens are related to various types of cancer, including oral squamous cell carcinoma (OSCC). Allied to alcohol, tobacco contributes to the unfavorable outcome of the cases. Individual cancer susceptibility may be related to an expression of the enzymes that metabolize such carcinogens. The aim of this work is to evaluate the expression of the genes CYP1A1, CYP1B1, CYP2A6 and CYP2E1 on OSCC by qPCR. Samples were collected from 32 individuals with OSCC and 15 controls submitted to oral surgeries due to benign lesions. There were four groups: Smoker SCC group (n = 26), nonsmoker SCC group (n = 6), Smoker control group (n = 9) and nonsmoker control group (n = 6). The Fagerström Test for Cigarette Dependence (TFCD) was used to evaluate nicotinic dependence (ND) and AUDIT for the evaluation of alcohol consumption. There was a decrease in CYP1B1 gene expression in cases of SCC compared to controls. (P = 0.0018); smoker CCE and non-smoker control (p = 0.0079); smoker SCC with nonsmoker SCC (p = 0.0385) and between the four groups (p <0.0001). There was a decreased expression in CYP2A6 in the smoker SCC Group compared to the control group, but only one control group patient expressed this gene. There was an increased expression of CYP2E1 between the smoking and nonsmoking SCC groups (p = 0.0424). In conclusion, large interindividual variability was found in the study of the expression of the genes studied. There was greater expression of CYP1A1 and CYP2E1 in samples from... (Complete abstract click electronic access below) / Doutor

Submitted by Rosina Valeria Lanzellotti Mattiussi Teixeira (rosina.teixeira@unisantos.br) on 2015-04-28T12:44:29Z No. of bitstreams: 1 Victor Miguel Coutinho Fernandes.pdf: 1491721 bytes, checksum: 2c2467271922975844f9dcc9fc53afb8 (MD5) / Made available in DSpace on 2015-04-28T12:44:29Z (GMT). No. of bitstreams: 1 Victor Miguel Coutinho Fernandes.pdf: 1491721 bytes, checksum: 2c2467271922975844f9dcc9fc53afb8 (MD5) Previous issue date: 2013-09-24 / The Cutaneous Squamous Cell Carcinoma (SCC) is the second most common form of skin cancer in the white population worldwide. This carcinoma has shown steady increase in incidence worldwide. Thus, becoming an important public health problem because of its high morbidity and high health service costs. There are few studies evaluating the epidemiological profile of the SCC in the brazilian population and none has specifically been done in the state of Paraíba. OBJECTIVE: To verify the clinical and epidemiological profile of the SCC cases of patients treated at the main referral hospital for cancer treatment in the state of Paraiba from 2009 to 2011, taking into consideration peculiarities of the behavior of this tumor in males and females, as well as the regions the state is divided in. METHODS: A crosssectional study was conducted using secondary data such as sex, age, origin, degree of invasion and tumor differentiation, affected part of the body and largest tumor diameter. It was done a descriptive analysis and used the chi-square test, test to compare two percentages, U Mann-Whitney, Kruskal-Wallis and Dunn's multiple comparison tests. Association analyses were performed and comparison of percentages. The significance level was 5%. RESULTS: There were 1225 cases of SCC, with a 2:1 ratio between men and women (p<0,05), respectively. The average age was 69 years old and the majority of the cases ¿ 940 (77%) - occurred in patients over 60 years old. The sun-exposed regions of the body were the most affected ones with 996 (81,3%) tumors. The head and neck area was the most common place of SCC, with 900 (73,5%) lesions. Most of the identified tumors, i.e. 942 (77%), were of the invasive type; among these, 558 (59%) had moderate grade of differentiation. Men showed SCC in average four years earlier than women (68 vs 72 years). Their SCC was also more aggressive than those identified in women with a higher percentage of poorly differentiated tumors (8,0% vs. 4,2%) (p = 0,02). Besides, men showed a higher proportion of tumors than women when located in the ear (6,9% vs 3,1%) (p=0,048) and chest (15,9% vs 6,7%) (p<0,001). Women had a higher proportion of tumors than men in the lower limbs (7,0% vs 2,1%) (p <0,001). Most patients with tumors, i.e. 643 (52%), came from Zona da Mata ¿ the coastal area of the state. However, considering the regions of the state of Paraíba, there were no statistically significant differences regarding the size of tumors or the degree of invasion and histological differentiation. CONCLUSION: This study has a pioneer character considering it evaluated the profile of the SCC separately from Basal Cell Carcinoma (BCC) in the state of Paraíba. By doing this, it was possible to highlight clinical and epidemiological particularities of the SCC. Doctors and healthcare managers in the state of Paraiba may find the data produced through this study useful in order to take preventive, diagnostic and precocious treatment measures that may contribute to diminish the incidence and morbidity of this malignancy. / O Carcinoma Espinocelular Cutâneo (CEC) é a segunda forma de câncer de pele mais frequente na população branca mundial. Este tumor vem apresentando aumento crescente da incidência em todo o mundo, constituindo-se importante problema de saúde pública devido à sua alta morbidade e aos elevados custos aos serviços de saúde. Existem poucos estudos avaliando o perfil epidemiológico do CEC na população brasileira e nenhum, especificamente, no estado da Paraíba. OBJETIVO: Verificar o perfil clínico-epidemiológico dos casos de CEC dos pacientes atendidos no principal hospital de referência no tratamento do câncer do estado da Paraíba nos 2009 a 2011, observando peculiaridades do comportamento deste tumor nos sexos masculino e feminino, bem como nas mesorregiões que compõem o estado. MÉTODO: Foi realizado um estudo transversal com dados secundários, analisando variáveis como: sexo, idade, procedência, grau de invasão e diferenciação histológica do tumor, local do corpo acometido e tamanho do tumor. Foi realizada análise descritiva e utilizado os testes de qui-quadrado, comparação entre duas porcentagens, teste U de Mann-Whitney, Kruskal-Wallis e teste de comparações múltiplas de Dunn. O nível de significância foi de 5%. RESULTADOS: Foram encontrados 1225 casos de CEC, com uma relação de 2:1 entre homens e mulheres (p<0,05), respectivamente. A média das idades foi de 69 anos, com a maioria - 940 (77%) - dos casos ocorridos em pacientes com mais de 60 anos de idade. As regiões fotoexpostas foram as mais acometidas com 996 (81,3%) tumores. A região da cabeça e pescoço foi a mais comum para o CEC com 900 (73,5%) lesões. A maioria dos tumores identificados foram invasivos ¿ ou seja, 942 (77%) casos ¿ dentre esses, 558 (59%) tinham grau de diferenciação moderado. Os homens apresentaram CEC em média quatro anos antes que as mulheres (68 vs 72 anos). Seus CEC também foram mais agressivos com maior percentual de tumores pouco diferenciados (8,0% vs 4,2%) (p=0,02). Além disso, o sexo masculino apresentou maior proporção de tumores que mulheres quando localizados na orelha (6,9% vs 3,1%) (p=0,048) e no tórax (15,9% vs 6,7%) (p<0,001). As mulheres apresentaram maior proporção de tumores em membros inferiores (7,0% vs 2,1%) (p<0,001). A maioria dos tumores, isto é, 643 (52%) dos casos, veio da Zona da Mata, no litoral do estado. Entretanto, considerando as mesorregiões da Paraíba, não houve diferenças estatisticamente significantes entre as mesmas quanto aos tamanhos de tumores, nem associação estatisticamente significante quanto aos graus de invasão e diferenciação histológica. CONCLUSÃO: O estudo foi pioneiro ao avaliar o perfil do CEC separadamente do Carcinoma Basocelular (CBC) no estado da Paraíba, o que permitiu constatar particularidades clínicas e epidemiológicas desse tumor. Espera-se que os dados obtidos sejam úteis às equipes médicas e aos gestores da saúde no estado da Paraíba para que sejam tomadas medidas de prevenção, diagnóstico e tratamentos precoces que contribuam para a diminuição da incidência e morbimortalidade desta neoplasia.

Cancer, a disease of an uncontrolled cell division, growth and metastasis as a result of genetic mutations, environmental factors and host response, is affecting populations worldwide. Etiology, pathogenicity, and genetics related to cancer are not well understood, and treatment has not been as effective as scientists have expected. Continual research is being done to improve current understanding and treatments. Oral squamous cell carcinoma (OSCC) is one of the most common head and neck cancers (representing >90 % of all head and neck cancers) involving neoplasms of the oral cavity and oropharynx. OSCC is a very pernicious malignancy developed from epithelial cells. There is evidence that a key N-glycosylation gene, DPAGT1, is associated with cancer. Although N-glycosylation of proteins is involved in organ development and homeostasis of tissue, overexpression of DPAGT1 has been implicated in oral cancer initiation and metastasis. Defects in N-glycosylation underlie congenital disorders, while hyper-N-glycosylation has been shown to be a feature of many cancers. The N-glycosylation pathway directs cell adhesion and cytoskeletal dynamics by impacting the function of E-cadherin, a major epithelial cell-cell adhesion receptor. E-cadherin is a tumor suppressor responsible for the organization of multiprotein complexes named adherens junctions (AJs). In epithelial cells, stable AJs are essential for several cellular processes, including inhibition of cell proliferation, reorganization of the actin cytoskeleton, and maintenance of an epithelial phenotype. Indeed, restoration of AJs has been shown to revert cancer cells from a mesenchymal to an epithelial phenotype and to reduce invasiveness. Previous work has shown that upregulation of DPAGT1 plays a pivotal role in driving canonical WNT/β-catenin signaling (also known as canonical Wnt signaling) that represses E-cadherin adhesions and drives tumorigenic phenotypes in oral cancer. This suggests a role in coordinating balance between proliferation and adhesion by DPAGT1. To date, little is known about the molecular and cellular details underlying differences among OSCC cell lines. CAL 27 and HSC-3 are human cancer cell lines commonly used to in laboratory OSCC research. The main differences between these cell lines include capsular tumors formed by CAL27 cells in nude mouse models in contrast to non-capsular and invasive tumors formed by HSC-3 cells. The goal of this study was to characterize biochemical differences between these two cell lines for further research.

HOXA7 belongs to a family of homeobox transcription factors that are master regulators of cell differentiation, morphogenesis during embryonic development and cell proliferation. Dysregulation and non-nuclear localization of these proteins play a role in a large number of solid tumours, with reports of significant upregulation of HOXA7 in oral dysplasia. It is unclear whether HOXA7 induction in solid tumours is causative or if it is a result of oncogenic changes. In this thesis we studied its effect on cell differentiation, growth, stemness, cell migration, EMT and cell senescence. The main hypothesis was that HOXA7 regulated keratinocyte differentiation through the regulation of activator protein 1 (AP-1), a keratinocyte specific activator of differentiation. We also hypothesised that HOXA7 increased the proliferation rate in keratinocytes. In an AP-1 reporter assay in HEK293 cells, HOXA7 was shown to decrease AP-1 activity significantly. The inactivation of AP-1 was not due to inactivation of PKC, as HOXA7 did not interfere with the activation of the kinases in HEK293. More specifically, we reported a very significant repression of c-Jun and JunD promoter activity in the presence of ectopic HOXA7 in HEK293 cells. We further showed that this mechanism might also be applicable in keratinocytes, as HOXA7 inhibited the transcription of AP-1 subunits of both the Jun and Fos family in skin keratinocytes. Furthermore, we showed transcriptional repression of four differentiation markers and a downregulation of K1 and FLG protein in transduced NEB-1 monolayers as well as K1 suppression in HaCaT cells. The organotypic cultures revealed a downregulation of K1, K10, and filaggrin in stratified HaCaT cells by HOXA7. There was however no downregulation in oral keratinocytes. These observations taken together suggested that HOXA7 repressed the synthesis of AP-1 units in skin keratinocytes, which would have resulted in reduced quantities of AP-1 and therefore lower activity. Contrary to previous reports, we observed no positive involvement of HOXA7 in keratinocyte proliferation, EMT or migration. There was however an indication of cell-type specific MET and induced cell senescence. Based on our results we propose a cell-type specific role of HOXA7 as an antagonist of AP-1 transcription in skin keratinocytes, and a possible direct binding of HOXA7 to c-Jun and JunD promoters.