Faria Márcia, Matos Paulo, Pereira Teresa, Cabrera Rafael, Cardoso Bruno A, Bugalho Maria João, Silva Ana Luísa
Unidade de Investigação de Patobiologia Molecular, Instituto Português de Oncologia de Lisboa Francisco Gentil E.P.E., Lisboa, Portugal.
BioISI-Biosystems and Integrative Sciences Institute, Faculdade de Ciências da Universidade de Lisboa, Portugal.
PLoS One. 2017 Feb 24;12(2):e0172689. doi: 10.1371/journal.pone.0172689. eCollection 2017.
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.
肿瘤相关的RAC1b过表达最近被强调为结肠癌、乳腺癌、肺癌和胰腺癌治疗干预最有前景的靶点之一。RAC1b是小GTP酶RAC1的一种高活性变体，最近已显示在一部分与不良预后相关的甲状腺乳头状癌中过表达。使用源自K1甲状腺乳头状癌的细胞系作为体外模型，我们观察到RAC1和RAC1b均能显著增加NF-κB和细胞周期蛋白D1报告基因的活性。在转染了RAC1b-WT的细胞中发现了明显的p65核定位，证实了NF-κB经典途径的激活。一致地，我们观察到RAC1b介导的IκBα（NF-κB抑制剂）蛋白水平降低。此外，我们表明RAC1b过表达刺激G1/S期进程并保护甲状腺细胞免受诱导的凋亡，后者通过涉及NF-κB途径的过程实现。目前的数据支持先前的研究结果，表明RAC1b在滤泡细胞源性甲状腺恶性肿瘤的发生发展中起重要作用，并指出NF-κB激活是与RAC1b在甲状腺癌中过表达的促肿瘤优势相关的分子机制之一。
