MicroRNA-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer.
Nuclear Factor kappa B (NF-κB) signaling is frequently deregulated in a variety of cancers and is constitutively active in estrogen receptor negative (ER-) breast cancer subtypes. These molecular subtypes of breast cancer are associated with poor overall survival. We focused on mechanisms of NF-κB regulation by microRNAs (miRNAs), which regulate eukaryotic gene expression at the post-transcriptional level. In a previous genome-wide miRNA screen, we had identified miR-30c-2-3p as one of the strongest negative regulators of NF-κB signaling. Here we have uncovered the underlying molecular mechanisms and its consequences in breast cancer. In vitro results show that miR-30c-2-3p directly targets both TNFRSF1A-associated via death domain (TRADD), an adaptor protein of the TNFR/NF-κB signaling pathway, and the cell cycle protein Cyclin E1 (CCNE1). Ectopic expression of miR-30c-2-3p downregulated essential cytokines IL8, IL6, CXCL1, and reduced cell proliferation as well as invasion in MDA-MB-231 breast cancer cells. RNA interference (RNAi) induced silencing of TRADD phenocopied the effects on invasion and cytokine expression caused by miR-30c-2-3p, while inhibition of CCNE1 phenocopied the effects on cell proliferation. We further confirmed the tumor suppressive role of this miRNA using a dataset of 781 breast tumors, where higher expression was associated with better survival in breast cancer patients. In summary we have elucidated the mechanism by which miR-30c-2-3p negatively regulates NF-κB signaling and cell cycle progression in breast cancer.
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany. Electronic address: kirti.iitr@gmail.com.
Kirti
K
Shukla
Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.
Ashwini Kumar
AK
Sharma
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany.
Aoife
A
Ward
Genomics & Proteomics Core Facility, DKFZ, 69120 Heidelberg, Germany.
Rainer
R
Will
Division of Biostatistics, DKFZ, 69120 Heidelberg, Germany.
Thomas
T
Hielscher
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany.
Aleksandra
A
Balwierz
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany.
Christian
C
Breunig
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany.
Ewald
E
Münstermann
Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Erlanger Allee 101, 07747 Jena, Germany; Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Beutenbergstrasse 11a, 07745 Jena, Germany; Division of Theoretical Bioinformatics, DKFZ, 69120 Heidelberg, Germany.
Rainer
R
König
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany.
Ioanna
I
Keklikoglou
Division of Molecular Genome Analysis, DKFZ, 69120 Heidelberg, Germany. Electronic address: s.wiemann@dkfz.de.
Stefan
S
Wiemann
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000235:genetics / Q000378:metabolism*
C475820:CCNE1 protein, human; D019927:Cyclin E; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D015513:Oncogene Proteins; D012334:RNA, Neoplasm; D053199:TNF Receptor-Associated Death Domain Protein
Breast cancer; Cell cycle progression; MicroRNA; NF-κB signaling