Overexpression of RAC1b in follicular cell derived thyroid cancers: An activator of NF-κB pathway that contributes to thyroid tumorigenesis?

• Autor(a) principal: Faria, Márcia Carina da Silva
• Data de Publicação: 2015
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/61263
• topic: Thyroid tumorigenesis; RAC1b; NF-κB canonical pathway; Cyclin D1; Apoptosis; Cell Cycle; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Papillary and Follicular thyroid carcinomas (PTC and FTC) are lesions derived from follicular cells. The standard therapy includes surgery and radioiodine treatment. Despite being usually associated with a good prognosis the rate of recurrence is high and a subset of patients present radioiodine refractory and non-responsive neoplasia. So, the search for new therapeutic alternatives, as well as new diagnostic/prognostic markers is highly relevant. Our group at IPOLFG has previously shown RAC1b to be overexpressed in PTCs, being this overexpression significantly associated with poorer outcomes. RAC1b is a variant of the small GTPase RAC1 that was shown to have the ability to stimulate the canonical NF-κB regulatory pathway in colorectal cancer. NF-κB activation is associated with the tumorigenic process in several types of cancer, mainly due to its role in apoptosis evasion. Here, we aimed to extend the study of the role of RAC1b to FTCs and further investigate the molecular mechanisms associated with RAC1b overexpression and downstream signalling in thyroid tumorigenesis. Using the human papillary thyroid carcinoma derived cell line as in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-κB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-κB canonical pathway activation. Consistently, we were able to observe a RAC1b-mediated decrease in IκBα (NF-κB inhibitor) protein levels. These findings prompted us to further assess the cellular consequences of RAC1b-mediated NF-κB activation in a thyroid biological system. Our results indicated that RAC1b protected cells against apoptosis and stimulated G1/S progression, through a process involving the NF-κB pathway. Summing up, presented findings suggest an important role of RAC1b in the progression of follicular cell derived thyroid carcinomas and point out NF-κB activation as one of the molecular mechanisms associated with RAC1b overexpression and downstream signalling in thyroid tumorigenesis.