RESUMO
Persistent infection with high-risk HPV is the etiologic agent associated with the development of cervical cancer (CC) development. However, environmental, social, epidemiological, genetic, and host factors may have a joint influence on the risk of disease progression. Cervical lesions caused by HPV infection can be removed naturally by the host immune response and only a small percentage may progress to cancer; thus, the immune response is essential for the control of precursor lesions and CC. We present a review of recent research on the molecular mechanisms that allow HPV-infected cells to evade immune surveillance and potential targets of molecular therapy to inhibit tumor immune escape.
RESUMO
It has been found that certain cytokines (IL-4, IL-10 and TGF-ß1) are highly expressed locally in biopsies from patients with premalignant lesions and cervical cancer, and may induce a local immune-suppression state. In particular, IL-10 is highly expressed in tumor cells and its expression is directly proportional to the development of HPV-positive cervical cancer, suggesting an important role of HPV proteins in the expression of IL-10. In fact, we demonstrated that E6 and E7 HPV proteins regulate TGF-ß1 gene expression in cervical cancer cells. Here, we found by band shifting analysis that the HPV E2 protein binds to the regulatory region of the human IL-10 gene (-2054 nt) and induces high promoter activity in epithelial cells. Additionally, cervical cancer cells transfected to express the HPV E2 protein induce elevated levels of IL-10 mRNA in human papillomavirus-infected cells. The elevated expression of IL-10 may allow for virus persistency, the transformation of cervical epithelial cells, and consequently cancer development.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Interleucina-10/genética , Proteínas Oncogênicas Virais/metabolismo , Neoplasias do Colo do Útero/genética , Sequência de Bases , Linhagem Celular Tumoral , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Humanos , Interleucina-10/metabolismo , Dados de Sequência Molecular , Regiões Promotoras Genéticas/genética , Ativação Transcricional/genéticaRESUMO
OBJECTIVE: Our aims were to examine the ability of the human papillomaviruse (HPV) 16 E2 protein to induce apoptosis in a murine HPV-transformed cell line, and to evaluate its antitumor properties on HPV-associated tumors in vivo in immunocompetent mice. METHODS: HPV-transformed murine BMK-16/myc cells and human SiHa cells were transfected with the HPV 16 E2 gene to examine the effects of the E2 protein on cell growth and on the E6 and E7 oncogenes as well as DNA fragmentation and activation of the extrinsic pathway of apoptosis. Finally, to test the antitumor effect of the E2 protein on an experimental mouse tumor model, we generated a recombinant adenovirus expressing the E2 protein. RESULTS: The E2 protein inhibited the growth of SiHa and BMK-16/myc cell lines, and repressed the E6 and E7 oncogenes. Moreover, the E2 protein induced DNA fragmentation and apoptosis through activation of caspases 8 and 3 in BMK-16/myc cells. On the other hand, E2 also showed antitumor effects in vivo. CONCLUSIONS: Our findings indicate that E2 exerts pro-apoptotic activity in a murine HPV-transformed cell line as well as an antitumor effect in vivo.
Assuntos
Apoptose , Transformação Celular Viral , Proteínas de Ligação a DNA/metabolismo , Terapia Genética , Papillomavirus Humano 16/fisiologia , Neoplasias/terapia , Proteínas Oncogênicas Virais/metabolismo , Adenoviridae/genética , Adenoviridae/metabolismo , Animais , Linhagem Celular Transformada , Linhagem Celular Tumoral , Fragmentação do DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/uso terapêutico , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Feminino , Vetores Genéticos/genética , Vetores Genéticos/metabolismo , Papillomavirus Humano 16/genética , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/virologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/uso terapêuticoRESUMO
Transforming growth factor beta-1 (TGF-beta 1) is produced by several cell lineages such as lymphocytes, macrophages, and dendritic cells, and its expression serves in both autocrine and paracrine modes to control the differentiation, proliferation, and state of activation of these and other cells. In general, TGF-beta 1 has pleiotropic properties on the immune response during the development of infection diseases and cancer; however, the mechanisms of action and regulation of gene expression of this cytokine are poorly understood, in this review, the biological properties and the molecular mechanisms that regulate TGF-beta 1 gene expression are described, to understand the role of this cytokine in growth and cell differentiation. The knowledge of molecular mechanisms of gene expression of TGF-beta 1 may serve to develop new cancer therapies. The English version of this paper is available at: http://www.insp.mx/salud/index.html
Assuntos
Neoplasias/imunologia , Fator de Crescimento Transformador beta/fisiologia , Ciclo Celular/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Isoformas de Proteínas/fisiologia , Transdução de SinaisRESUMO
Several genetic alterations occur during the transformation process from normal to tumor cells, that involve the loss of fidelity of processes as replication, reparation, and segregation of the genomic material. Although normal cells have defense mechanisms against cancer progression, in tumor cells different escape pathways are activated leading to tumor progression. Recent advances have permitted cancer research to focus on the identification of some of its etiological factors. The knowledge of cell cycle reveals a precise mechanism achieved by the coordinated interactions and functions of cyclin-dependent kinases, control checkpoint, and repair pathways. Furthermore, it has been demonstrated that this coordinated function can be abrogated by specific genetic changes. These findings suggest that the molecular mechanisms responsible for cellular transformation may help to identify potential targets to improve cancer therapies.
Assuntos
Transformação Celular Neoplásica/patologia , Neoplasias Experimentais/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/metabolismo , Genes do Retinoblastoma/fisiologia , Humanos , Neoplasias/etiologia , Neoplasias/prevenção & controle , Neoplasias Experimentais/etiologia , Neoplasias Experimentais/prevenção & controle , Transcrição Gênica/fisiologia , Proteína Supressora de Tumor p53/fisiologiaRESUMO
The T lymphocytes recognize antigens through antigen receptors (TcRs) and the major histocompatibility complex (MHC) molecules: they lysate the cells that bear the antigen, or release cytokines that are mediators of the immune response. The TcRs recognize antigens in the form of short peptides bound to MHC molecules. So far, there are two isotypes of TcR: gamma/delta and alpha/beta, which appear in the sequence during T-cell ontogeny. The process of selection of TcRs during thymic ontogeny obeys to molecular mechanisms which generate intracellular events that will participate in the gene expression of the TcR. The aim of the present paper is to review the molecular, structural, and functional aspects of the TcRs, and their role in human autoimmune infectious disease.
Assuntos
Doenças Autoimunes/imunologia , Infecções/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Protozoários/imunologia , Antígenos Virais/imunologia , Citotoxicidade Imunológica , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Linfócitos T/metabolismoRESUMO
The immune system is a tight network of different types of cells and molecules. The coordinated action of these elements mounts a precise immune response against tumor cells. However, these cells present several escape mechanisms, leading to tumor progression. This paper shows several cellular and molecular events involved in the regulation of the immune response against tumor cells. The interaction of several molecules such as MHC, TcR, adhesins, tumor antigens and cytokines are discussed, as well as the most recent knowledge about escape mechanisms and immunotherapy.
Assuntos
Neoplasias/imunologia , Antígenos de Neoplasias/imunologia , Adesão Celular , Fatores Estimuladores de Colônias/imunologia , Humanos , Imunoterapia , Imunoterapia Ativa , Interferons/imunologia , Interleucinas/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Neoplasias/patologia , Neoplasias/terapia , Receptores de Antígenos/imunologia , Linfócitos T/imunologia , Evasão Tumoral , Fator de Necrose Tumoral alfa/imunologiaRESUMO
In this paper the molecular aspects of the relationships between infectious agents and autoimmune diseases, the mechanisms of immune response to infectious agents, and the more recent hypotheses regarding the cause of autoimmune diseases are discussed. The antigens are processed and selected by their immunogenicity, and presented by HLA molecules to the T cell receptor. These events initiate the immune response with the activation and proliferation of T-lymphocytes. Although there are several hypotheses regarding the cause of autoimmune diseases and too many findings against and in favor of them, there is still no conclusive data. All these hypothesis and findings are discussed in the context of the more recent advances.