Carcinogênese da próstata de camundongos: papel do receptor tipo I do TNF-α na incidência tumoral

• Autor(a) principal: Galheigo, Maria Raquel Unterkircher
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFU
• Texto Completo: https://repositorio.ufu.br/handle/123456789/12415; https://doi.org/10.14393/ufu.di.2015.444
• topic: TNFR-1; Carcinogênese da próstata; AKT/mTOR; Próstata - Câncer; Citocinas; Prostate carcinogenesis; CNPQ::CIENCIAS BIOLOGICAS::MORFOLOGIA::CITOLOGIA E BIOLOGIA CELULAR

TNF-α is a key cytokine involved in process of carcinogenesis, including prostate cacrinogenesis, being TNFR-1 the responsible for the majority of its answers. This receptor triggers two opposite pathways: cell death or cell survival. So, due to this paradoxal role, a TNFR-1 knockout model is interesting in order to clarify the real effect of TNF in prostate cancer. Thus, this investigation had as a general propose to evaluate the role of TNF signalling pathway in prostate carcinogenesis by chemical induction in mice. Therefore, C57bl/6 wild type (WT) and TNFR-1 knockout mice (KO) were treated with mineral oil or MNU in association with testosterone (MNU+T) during 6 months. After this period of induction, prostate samples were processed for histological and biochemical analysis. It was observed that the treatment with MNU+T led to development of benign and malign lesions in both WT e KO animals. However, the incidence of malign lesions was significantly higher in the former, indicating the involvement of TNFR-1 with cellular survival and proliferation pathaway. These data were supported by proliferative profile analysis, which showed that proloferation was significantly lower in KO, even after carcinogenesis. Moreover, knockout animals had smaller prostate amounts of mTOR after treatment with MNU+T in comparison to WT, suggesting the potential of TNFR-1 in activating this proliferative pathway. It was also observed a decrease in AR quantities in prostate after carcinogenesis in both KO and WT. Since AR expression may be regulated as a result of PI3K/AKT/mTOR pathway activation, it is suggested that the decrease of AR in KO may have occurred as a result of smaller quantities of mTOR in these animals. Moreover, it s suggested that TNF-α /TNFR-1 has key role in MMP2 expression, reducing the content of this enzyme in its absence, and that the decrease of MMP2 may be responsible to the accumulation of fibronectin in KO. Finally, it was observed a similar increase in apoptosis in WT and KO group after carcinogenesis, showing clearly that TNFR-1 in this model was not involved in the induction of cell death. Therefore, it is concluded that the cytokine TNF-α, through its receptor TNFR-1 promoted cell proliferation and cell survival by activation of the AKT/mTOR pathway, which implicates its role in prostate carcinogenesis in this experimental model.