Buck Institute for Age Research, Novato, CA 94945, USA.
Oncogene. 2008 Sep 18;27(42):5643-7. doi: 10.1038/onc.2008.171. Epub 2008 May 26.
Cancer cells often acquire a constitutively active nuclear factor-kappaB (NF-kappaB) program to promote survival, proliferation and metastatic potential by mechanisms that remain largely unknown. Extending observations from an immunologic setting, we demonstrate that microRNA-146a and microRNA-146b (miR-146a/b) when expressed in the highly metastatic human breast cancer cell line MDA-MB-231 function to negatively regulate NF-kappaB activity. Lentiviral-mediated expression of miR-146a/b significantly downregulated interleukin (IL)-1 receptor-associated kinase and TNF receptor-associated factor 6, two key adaptor/scaffold proteins in the IL-1 and Toll-like receptor signaling pathway, known to positively regulate NF-kappaB activity. Impaired NF-kappaB activity was evident from reduced phosphorylation of the NF-kappaB inhibitor IkappaBalpha, reduced NF-kappaB DNA-binding activity and suppressed expression of the NF-kappaB target genes IL-8, IL-6 and matrix metalloproteinase-9. Functionally, miR-146a/b-expressing MDA-MB-231 cells showed markedly impaired invasion and migration capacity relative to control cells. These findings implicate miR-146a/b as a negative regulator of constitutive NF-kappaB activity in a breast cancer setting and suggest that modulating miR-146a/b levels has therapeutic potential to suppress breast cancer metastases.
癌细胞通常会获得一个组成性激活的核因子-κB（NF-κB）程序，通过机制来促进生存、增殖和转移潜能，这些机制在很大程度上尚不清楚。从免疫学的角度来看，我们的研究结果表明，在高转移性的人类乳腺癌细胞系 MDA-MB-231 中表达 microRNA-146a 和 microRNA-146b（miR-146a/b）可以负调控 NF-κB 活性。慢病毒介导的 miR-146a/b 表达显著下调白细胞介素（IL）-1 受体相关激酶和肿瘤坏死因子受体相关因子 6，这两种蛋白是 IL-1 和 Toll 样受体信号通路中的关键衔接蛋白/支架蛋白，已知它们可以正向调节 NF-κB 活性。NF-κB 抑制剂 IkappaBalpha 的磷酸化减少、NF-κB DNA 结合活性降低以及 NF-κB 靶基因 IL-8、IL-6 和基质金属蛋白酶-9 的表达受到抑制，这些都表明 NF-κB 活性受损。功能上，与对照细胞相比，表达 miR-146a/b 的 MDA-MB-231 细胞的侵袭和迁移能力明显受损。这些发现表明 miR-146a/b 是乳腺癌中 NF-κB 活性的负调节剂，并表明调节 miR-146a/b 的水平具有抑制乳腺癌转移的治疗潜力。
