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  • 1
    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.
    Type of Publication: Journal article published
    PubMed ID: 25500542
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  • 2
    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.
    Type of Publication: Journal article published
    PubMed ID: 23364795
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  • 3
    Abstract: BACKGROUND: miRNAs are small noncoding RNA molecules that play an important role in post-transcriptional regulation of gene expression. Length and/or sequence variants of the same miRNA are termed isomiRs. While most isomiRs are functionally redundant compared to their canonical counterparts, the so-called 5'isomiRs exhibit a shifted 5' end and therefore a shifted seed sequence resulting in a different target spectrum. However, not much is known about the functional relevance of these isoforms. RESULTS: Analysis of miRNA-seq data from breast cancer cell lines identified six pairs of highly expressed miRNAs and associated 5'isomiRs. Among them, hsa-miR-140-3p was of particular interest because its 5'isomiR showed higher expression compared to the canonical miRNA annotated in miRbase. This miRNA has previously been shown to control stemness of breast cancer cells. miRNAseq data of breast cancer patients (TCGA dataset) showed that both the canonical hsa-miR-140-3p and its 5'isomiR-140-3p were highly expressed in patients' tumors compared to normal breast tissue. In the current work, we present the functional characterization of 5'isomiR-140-3p and the cellular phenotypes associated with its overexpression in MCF10A, MDA-MB-468 and MDA-MB-231 cell lines in comparison to the canonical hsa-miR-140-3p. Contrary to the effect of the canonical hsa-miR-140-3p, overexpression of the 5'isomiR-140-3p led to a decrease in cell viability. The latter observation was supported by cell cycle analysis, where the 5'isomiR-140-3p but not the hsa-miR-140-3p caused cell cycle arrest in G0/G1-phase. Additionally, 5'ismoiR-140-3p overexpression was found to cause a decrease in cell migration in the three cell lines. We identified three novel direct target genes of the 5'isomiR-140-3p; COL4A1, ITGA6 and MARCKSL1. Finally, we have shown that knocking down these genes partially phenocopied the effects of the 5'isomiR-140-4p overexpression, where COL4A1 and ITGA6 knockdown led to reduced cell viability and cell cycle arrest, while MARCKSL1 knockdown resulted in a decrease in the migratory potential of cells. CONCLUSIONS: In summary, this work presents evidence that there is functional synergy between the canonical hsa-miR-140-3p and the newly identified 5'isomiR-140-3p in suppressing growth and progression of breast cancer by simultaneously targeting genes related to differentiation, proliferation, and migration.
    Type of Publication: Journal article published
    PubMed ID: 27502506
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  • 4
    Abstract: The tumor microenvironment (TME) has an impact on breast cancer progression by creating a pro-inflammatory milieu within the tumor. However, little is known about the roles of miRNAs in cells of the TME during this process. We identified six putative oncomiRs in a breast cancer dataset, all strongly correlating with poor overall patient survival. Out of the six candidates, miR-1246 was upregulated in aggressive breast cancer subtypes and expressed at highest levels in mesenchymal stem/stroma cells (MSCs). Functionally, miR-1246 led to a p65-dependent increase in transcription and release of pro-inflammatory mediators IL-6, CCL2 and CCL5 in MSCs, and increased NF-kappaB activity. The pro-inflammatory phenotype of miR-1246 in MSCs was independent of TNFalpha stimulations and mediated by direct targeting of the tumor-suppressors PRKAR1A and PPP2CB. In vitro recapitulation of the TME revealed increased Stat3 phosphorylation in breast epithelial (MCF10A) and cancer cells (SK-BR-3, MCF7, T47D) upon incubation with conditioned medium (CM) of MSCs overexpressing miR-1246. Additionally, this stimulation enhanced proliferation of MCF10A cells, increased migration of MDA-MB-231 cells and induced attraction of THP-1 monocytic cells. Our data shows that miR-1246 acts as both key-enhancer of pro-inflammatory responses in MSCs and putative oncomiR in breast cancer, suggesting its influence on cancer-related inflammation and breast cancer progression.
    Type of Publication: Journal article published
    PubMed ID: 28159925
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  • 5
    Keywords: GENE ; CANCER ; CELL ; IDENTIFICATION ; LINE ; CELL-LINE ; ONCOLOGY ; HUMAN CANCER ; EFFECTOR ; CANCERS
    Type of Publication: Meeting abstract published
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  • 6
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    Zeitschrift für anorganische Chemie 535 (1986), S. 123-134 
    ISSN: 0044-2313
    Keywords: Chemistry ; Inorganic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Bestimmung der Sublimation und Dissoziation von ThI4 und ThOI2 nach der Knudsen-MethodeDer Sublimationsdruck von ThI4 ergibt sich aus Messungen nach der Knudsen-Methode zu \documentclass{article}\pagestyle{empty}\begin{document}$$ \lg {\rm p/bar} = - 11200/{\rm T} - 4,57{\rm lg T} + 24,81 $$\end{document}. Mit der Sublimation von ThI4 erfolgt simultan eine geringe Dissoziation zu niederwertigem Iodid und Iod. Der Dissoziationsdruck des ThOI2 gemäß 2 ThOI2 = ThO2 + ThI4 ergibt sich, ebenfalls nach Effusionsmessungen, zu \documentclass{article}\pagestyle{empty}\begin{document}$$ \lg {\rm p/bar} = - 15490/{\rm T} - 4,57\lg {\rm T} + 25,85 $$\end{document} Die Molwärme von festem ThI4 wird kalorimetrisch zu 146 J K-1 mol-1 bestimmt, die Schmelzenthalpie zu rund 48 kJ mol-1. Die Normalentropie von festem ThOI2 ergibt sich zu 145 J K-1 mol-1.
    Notes: The sublimation pressure of ThI4 has been measured by the Knudsen effusion method and found to be \documentclass{article}\pagestyle{empty}\begin{document}$$ \lg {\rm p/bar} = - 11200/{\rm T} - 4.57{\rm lg T} + 24.81 $$\end{document}. Simultaneously with the sublimation of ThI4 there is a small dissociation to lower iodide and iodine. The dissociation pressure associated with the reaction 2 ThOI2 = ThO2 + ThI4 is \documentclass{article}\pagestyle{empty}\begin{document}$$ \lg {\rm p/bar} = - 15490/{\rm T} - 4.57\lg {\rm T} + 25.85 $$\end{document} The molar heat capacity of solid ThI4 has been determined calorimetrically to be 146 J K-1 mol-1, the heat of fusion is approximately 48 kJ mol-1. The standard entropy of solid ThOI2 is calculated to be 145 J K-1 mol-1.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1435-1536
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics
    Type of Medium: Electronic Resource
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