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  • proliferation  (2)
  • Breast Neoplasms/*drug therapy/*pathology  (1)
  • 1
    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
    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: 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.
    Type of Publication: Journal article published
    PubMed ID: 22158050
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  • 4
    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="" 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
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