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  • EXPRESSION  (4)
  • NF-KAPPA-B  (2)
  • Breast Neoplasms/*drug therapy/*pathology  (1)
  • CANCER-CELLS  (1)
  • 1
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    MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes
    Oncogene 34 (37), 4867-4878 
    Details
    Keywords: GROWTH ; LUNG-CANCER ; NF-KAPPA-B ; TRANSCRIPTION FACTOR ; mechanisms ; DUCTAL ADENOCARCINOMA ; TUMOR LYMPHANGIOGENESIS ; BREAST-CANCER METASTASIS ; HUMAN-ENDOTHELIAL-CELLS ; PROMOTES ANGIOGENESIS
    Abstract: Recent advances in cancer biology have emerged important roles for microRNAs (miRNAs) in regulating tumor responses. However, their function in mediating intercellular communication within the tumor microenvironment is thus far poorly explored. Here, we found miR-206 to be abrogated in human pancreatic ductal adenocarcinoma (PDAC) specimens and cell lines. We show that miR-206 directly targets the oncogenes KRAS and annexin a2 (ANXA2), thereby acting as tumor suppressor in PDAC cells by blocking cell cycle progression, cell proliferation, migration and invasion. Importantly, we identified miR-206 as a negative regulator of oncogenic KRAS-induced nuclear factor-kappa B transcriptional activity, resulting in a concomitant reduction of the expression and secretion of pro-angiogenic and pro-inflammatory factors including the cytokine interleukin-8, the chemokines (C-X-C motif) ligand 1 and (C-C motif) ligand 2, and the granulocyte macrophage colony-stimulating factor. We further show that miR-206 abrogates the expression and secretion of the potent pro-lymphangiogenic factor vascular endothelial growth factor C in pancreatic cancer cells through an NF-kappa B-independent mechanism. By using in vitro and in vivo approaches, we reveal that re-expression of miR-206 in PDAC cells is sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression. Taken together, our study sheds light onto the role of miR-206 as a pleiotropic modulator of different hallmarks of cancer, and as such raising the intriguing possibility that miR-206 may be an attractive candidate for miRNA-based anticancer therapies.
    DOI: 10.1038/onc.2014.408
    Type of Publication: Journal article published
    PubMed ID: 25500542
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=55347
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  • 2
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    MicroRNA-30c-2-3p negatively regulates NF-kappaB signaling and cell cycle progression through downregulation of TRADD and CCNE1 in breast cancer
    Molecular Oncology 9 (6), 1106-1119 
    Details
    Keywords: EXPRESSION ; GROWTH ; FACTOR RECEPTOR ; ACTIVATION ; TNF-ALPHA ; TUMOR-SUPPRESSOR ; MAMMARY-GLAND DEVELOPMENT ; TRANSDUCTION PATHWAYS ; MOLECULAR PORTRAITS ; OVARIAN-TUMORS
    Abstract: Nuclear Factor kappa B (NF-kappaB) 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-kappaB 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-kappaB 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-kappaB 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-kappaB signaling and cell cycle progression in breast cancer.
    DOI: 10.1016/j.molonc.2015.01.008
    Type of Publication: Journal article published
    PubMed ID: 25732226
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=61105
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  • 3
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    Rapid fluorescence imaging of miRNAs in human cells using templated Staudinger reaction
    Chemical Science 2 (10), 1969-1975 
    Details
    Keywords: CANCER ; CELLS ; EXPRESSION ; PATHWAYS ; QUANTIFICATION ; RNA ; DNA ; REDUCTION ; PEPTIDE NUCLEIC-ACIDS ; IN-SITU HYBRIDIZATION ; PROBES ; LIVING CELLS ; TARGETS ; REGULATORS ; miRNAs
    Abstract: It is generally accepted that microRNAs (miRNAs) play a crucial role in gene expression regulation and that their aberrant expression is intimately linked with pathologies, most notably cancer. There is thus significant interest in detecting and quantifying these important regulators. Herein, we report the fluorescence imaging of miRNAs within a few hours using a nucleic-acid templated Staudinger reaction. A good correlation between the level of miRNAs and the fluorescence intensity was observed across different cell lines. This method was shown to also be applicable for suspended cells with fluorescence quantification by flow cytometry
    Type of Publication: Journal article published
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=24755
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  • 4
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    MicroRNA-31 Sensitizes Human Breast Cells to Apoptosis by Direct Targeting of Protein Kinase C {epsilon} (PKC{epsilon})
    Journal of Biological Chemistry 288 (12), 8750-8761 
    Details
    Keywords: proliferation ; PATHWAY ; GENES ; NF-KAPPA-B ; ACTIVATION ; SUPPRESSION ; METASTASIS ; CANCER-CELLS ; TRANSCRIPTIONAL REGULATION ; MIR-31
    Abstract: MicroRNAs post-transcriptionally regulate gene expression and thereby contribute to the modulation of numerous complex and disease-relevant cellular phenotypes, including cell proliferation, cell motility, apoptosis, and stress response. In breast cancer cell systems, miR-31 has been shown to inhibit cell migration, invasion, and metastasis. Here, we link enhanced expression of miR-31 to the inhibition of the oncogenic NF-kappaB pathway, thus supporting the tumor-suppressive function of this microRNA. We identified protein kinase C epsilon (PKCepsilon encoded by the PRKCE gene) as a novel direct target of miR-31 and show that down-regulation of PKCepsilon results in impaired NF-kappaB signaling, enhanced apoptosis, and increased sensitivity of MCF10A breast epithelial and MDA-MB-231 triple-negative breast cancer cells toward ionizing radiation as well as treatment with chemotherapeutics. Mechanistically, we attribute this sensitization to anti-cancer treatments to the PRKCE-mediated down-regulation of the anti-apoptotic factor BCL2. In clinical breast cancer samples, high BCL2 expression was associated with poor prognosis. Furthermore, we found an inverse correlation between miR-31 and BCL2 expression, highlighting the functional relevance of the indirect down-regulation of BCL2 via direct targeting of PRKCE by miR-31.
    DOI: 10.1074/jbc.M112.414128
    Type of Publication: Journal article published
    PubMed ID: 23364795
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=39684
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  • 5
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    MicroRNA-200c represses migration and invasion of breast cancer cells by targeting actin-regulatory proteins FHOD1 and PPM1F
    Molecular and Cellular Biology 32 (3), 633-651 
    Details
    Keywords: EXPRESSION ; LINES ; DYNAMICS ; breast cancer ; REQUIRES ; SERUM RESPONSE FACTOR ; EPITHELIAL-MESENCHYMAL TRANSITION ; miR-200 family ; FORMIN ; FIBER FORMATION ; ZEB1
    Abstract: MicroRNA-200c (miR-200c) has been shown to suppress epithelial-to-mesenchymal transition (EMT), which is mainly attributed to targeting of ZEB1/ZEB2, repressors of the cell-cell contact protein E-Cadherin. Here, we demonstrated that modulation of miR-200c in breast cancer cells regulates cell migration, cell elongation and TGF-beta-induced stress fiber formation, by impacting the re-organization of cytoskeleton that is independent of the ZEB/E-Cadherin-axis. We identified FHOD1 and PPM1F, direct regulators of the actin cytoskeleton, as novel targets of miR-200c. Remarkably, expression levels of FHOD1 and PPM1F were inversely correlated with miR-200c in breast cancer cell lines, breast cancer patient samples, as well as in 58 cancer cell lines of various origin. Furthermore, individual knockdown/overexpression of these target genes phenocopied the effects of miR-200c overexpression/inhibition on cell elongation, stress fiber formation, migration and invasion. Mechanistically, targeting of FHOD1 by miR-200c resulted in decreased expression and transcriptional activity of SRF mediated by interference with the translocation of SRF co-activator MRTF-A. This finally led to downregulation of the expression and phosphorylation of the SRF target gene MLC2 required for stress fiber formation and contractility. Thus, miR-200c impacts on metastasis by regulating several EMT-related processes, including a novel mechanism involving the direct targeting of actin-regulatory proteins.
    Type of Publication: Journal article published
    PubMed ID: 22144583
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=27283
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  • 6
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    MicroRNA-520/373 family functions as a tumor suppressor in estrogen receptor negative breast cancer by targeting NF-kappaB and TGF-beta signaling pathways
    Oncogene 31 (37), 4150-4163 
    Details
    Keywords: ANGIOGENESIS ; EXPRESSION ; GROWTH-FACTOR ; INVASION ; proliferation ; ACTIVATION ; UP-REGULATION ; EMBRYONIC STEM-CELLS ; bone metastasis ; MicroRNAs
    Abstract: MicroRNAs (miRNAs) as modulators of gene expression have been described to display both tumor-promoting and tumor-suppressive functions. Although their role has been studied in different tumor types, little is known about how they regulate nuclear factor kappaB (NF-kappaB) signaling in breast cancer. Here, we performed an unbiased whole genome miRNA (miRome) screen to identify novel modulators of NF-kappaB pathway in breast cancer. The screen identified 13 miRNA families whose members induced consistent effects on NF-kappaB activity. Among those, the miR-520/373 family inhibited NF-kappaB signaling through direct targeting of RELA and thus strongly reduced expression and secretion of the pro-inflammatory cytokines interleukin (IL)-6 and IL-8. With a combination of in vitro and in vivo approaches, we propose a metastasis-suppressive role of miR-520/373 family. miR-520c and miR-373 abrogated both in vitro cell invasion and in vivo intravasation of highly invasive MDA-MB-231 cells. However, knockdown of RELA did not affect their metastatic ability. mRNA profiling of MDA-MB-231 cells on overexpression of miR-520/373 members revealed a strong downregulation of transforming growth factor-beta (TGF-beta) signaling. Mechanistically, the metastasis-suppressive role of miR-520/373 can be attributed to direct suppression of TGFBR2, as the silencing of TGFBR2 phenocopied the effects of miR-520/373 overexpression on suppression of Smad-dependent expression of the metastasis-promoting genes parathyroid hormone-related protein, plasminogen activator inhibitor-1 and angiopoietin-like 4 as well as tumor cell invasion, in vitro and in vivo. A negative correlation between miR-520c and TGFBR2 expression was observed in estrogen receptor negative (ER(-)) breast cancer patients but not in the ER positive (ER(+)) subtype. Remarkably, decreased expression of miR-520c correlated with lymph node metastasis specifically in ER(-) tumors. Taken together, our findings reveal that miR-520/373 family has a tumor-suppressive role in ER(-) breast cancer by acting as a link between the NF-kappaB and TGF-beta pathways and may thus contribute to the interplay of tumor progression, metastasis and inflammation.Oncogene advance online publication, 12 December 2011; doi:10.1038/onc.2011.571.
    DOI: 10.1038/onc.2011.571.
    Type of Publication: Journal article published
    PubMed ID: 22158050
    Deep Link: http://www.dkfz.de/cgi-bin/sel?http://www.dkfz.de/PublicationManager/Show/ShowJournal.aspx%3fpublishedId=27862
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  • 7
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    Cancer: Metastasis risk after anti-macrophage therapy (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-10-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keklikoglou, Ioanna -- De Palma, Michele -- England -- Nature. 2014 Nov 6;515(7525):46-7. doi: 10.1038/nature13931. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Swiss Institute for Experimental Cancer Research, School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337881" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*drug therapy/*pathology ; Chemokine CCL2/*antagonists & inhibitors/*metabolism ; Female ; *Neoplasm Metastasis ; *Neovascularization, Pathologic
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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