RAC1b promotes thyroid tumorigenesis via anti-apoptotic signaling

Authors and Affiliations:
Márcia Faria ¹, Paulo Matos ^5,6, Teresa Pereira ², Rafael Cabrera ², Bruno A Cardoso ¹, Maria João Bugalho ^3,4, Ana Luísa Silva ^1,3,4

¹-Unidade de Investigação de Patobiologia Molecular,

²-Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal;

³-Serviço de Endocrinologia, Diabetes e Metabolismo, do CHLN - Hospital Santa Maria, Lisboa, Portugal;

⁴-ISAMB – Instituto de Saúde Ambiental, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal;

⁵-BioISI – Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Portugal;

⁶-Instituto Nacional de Saúde, Doutor Ricardo Jorge, Lisboa, Portugal

Abstract:
Overexpression of tumor-associated RAC1b has been recently highlighted as one of the most promising targets for therapeutic intervention in colon, breast, lung and pancreatic cancer. RAC1b is a hyperactive variant of the small GTPase RAC1 and has been recently shown to be overexpressed in a subset of papillary thyroid carcinomas associated with unfavorable outcome. Using the K1 PTC derived cell line as an in vitro model, we observed that both RAC1 and RAC1b were able to induce a significant increase on NF-kB and cyclin D1 reporter activity. A clear p65 nuclear localization was found in cells transfected with RAC1b-WT, confirming NF-kB canonical pathway activation. Consistently, we observed a RAC1b-mediated decrease in IκBα (NF-kB inhibitor) protein levels. Moreover, we show that RAC1b overexpression stimulates G1/S progression and protects thyroid cells against induced apoptosis, the latter through a process involving the NF-kB pathway. Present data support previous findings suggesting an important role for RAC1b in the development of follicular cell-derived thyroid malignancies and point out NF-kB activation as one of the molecular mechanisms associated with the pro-tumorigenic advantage of RAC1b overexpression in thyroid carcinomas.

Journal: PLOS one

Link: http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172689