Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells.
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.
Bhaumik
D
D
Buck Institute for Age Research, Novato, CA 94945, USA.
Scott
G K
GK
Schokrpur
S
S
Patil
C K
CK
Campisi
J
J
Benz
C C
CC
D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D035683:MicroRNAs / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000502:physiology; D009362:Neoplasm Metastasis / Q000517:prevention & control*
D015850:Interleukin-6; D016209:Interleukin-8; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases