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So Yeon Park - One of the best experts on this subject based on the ideXlab platform.

  • prognostic value of microRNA 9 and microRNA 155 expression in triple negative breast cancer
    Human Pathology, 2017
    Co-Authors: Min Hye Jang, Hyun Jeong Kim, Jae Moon Gwak, Yul Ri Chung, So Yeon Park
    Abstract:

    microRNAs (miRNAs) are involved in regulation of epithelial-mesenchymal transition (EMT) during breast cancer progression. The purpose of this study was to analyze the clinicopathologic significance of expression of EMT-related miRNAs, miR-9 and miR-155, in triple-negative breast cancers (TNBCs). We analyzed relative expression levels of miR-9 and miR-155 in 190 surgically resected TNBC specimens using quantitative real-time polymerase chain reaction. Then we analyzed the relationship between these miRNA expression levels and EMT marker expression (vimentin, smooth muscle actin [SMA], osteonectin, N-cadherin, E-cadherin, CD146, and ZEB1) assessed by immunohistochemistry. We also evaluated the prognostic significance of these miRNA expression levels. While miR-9 expression level showed a positive correlation with pT category, miR-155 expression level did not correlate with any clinicopathologic features of TNBCs. In relation to EMT phenotype, miR-9 expression was not associated with EMT marker expression except for SMA. However, miR-155 expression level correlated inversely with the expression of several EMT markers including SMA, osteonectin, and CD146. We observed that both miR-9 and miR-155 could be prognostic markers in TNBC in opposite ways; high level of miR-9 expression showed significant association with poor disease-free survival and distant metastasis-free survival (DMFS) in TNBC, while high level of miR-155 expression was associated with better DMFS. Our study suggests that expression levels of both miR-9 and miR-155 can serve as candidates for prognostic biomarkers in TNBCs.

  • microRNA 9 is associated with epithelial mesenchymal transition breast cancer stem cell phenotype and tumor progression in breast cancer
    Breast Cancer Research and Treatment, 2014
    Co-Authors: Jae Moon Gwak, Hyun Jeong Kim, Yul Ri Chung, So Yeon Park, Eun Joo Kim, Sumi Yun, An Na Seo, Hee Jin Lee
    Abstract:

    microRNAs (miRNAs) are involved in the progression of breast cancer. Some miRNAs, especially the miR-200 family, miR-9, and miR-155 have been reported to be associated with epithelial-mesenchymal transition (EMT) and breast cancer stem cell (BCSC) phenotypes. This study was designed to evaluate the expression levels of these miRNAs in human breast cancer samples and analyzed their relationship with clinicopathologic features of the tumor including breast cancer subtype, EMT, BCSC phenotype, and prognosis. Expression levels of the miR-200 family, miR-9, and miR-155 were quantified using qRT-PCR. Breast cancer subtype, BCSC phenotype (CD44+/CD24− and ALDH1+), and expression of EMT markers (vimentin expression and E-cadherin loss) were evaluated by immunohistochemistry. miR-9 was more highly expressed in HER2+ and triple-negative subtypes than in luminal subtypes. Its expression level was significantly higher in tumors with high T stage, high histologic grade, p53 overexpression, and high proliferation index. Expression of miR-9 was also higher in tumors showing the CD44+/CD24− phenotype, vimentin expression, and E-cadherin loss. Furthermore, high level of miR-9 expression was found to be an independent prognostic factor for poor disease-free survival of the patients. Expression of miR-200a and miR-141 was highest in luminal A subtype, and miR-155 expression was highest in triple-negative subtype. Although the expression levels of some miR-200 family members and miR-155 showed difference with regard to EMT or BCSC phenotype, they were not associated with patients’ prognosis. In conclusion, overexpression of miR-9 is found in tumors with aggressive phenotypes and is associated with poor prognosis in breast cancer, suggesting that it may serve as a potential biomarker for breast cancer progression and a target for treatment.

Webster K Cavenee - One of the best experts on this subject based on the ideXlab platform.

  • mutant egfr suppression of microRNA 9 induces foxp1 to enhance glioblastoma tumorigenicity
    Neuro-oncology, 2014
    Co-Authors: Frank B Furnari, German Gomez, Stefano Volinia, Carlo M Croce, Ciro Zanca, Cameron Brennan, David Gutmann, Webster K Cavenee
    Abstract:

    BACKGROUND: Glioblastoma (GBM) frequently displays amplification and/or mutation of the epidermal growth factor receptor (EGFR) gene. Highlighting the importance of EGFR in the pathogenesis of GBM, aberrant EGFR (ΔEGFR, also known as EGFRvIII) confers a variety of biological effects upon its expression, including resistance to radiation and chemotherapeutic agents, promotion of tumor cell motility and invasion, enhancement of tumorigenicity in vivo, and maintenance of GBM growth and heterogeneity. We hypothesized that this diverse oncogenic pathophysiology exerted by ΔEGFR is regulated, in part, through the modulation of microRNA (miR) activity, widely shown to be involved in many biological processes including cancer initiation, maintenance and progression. METHODS: To test this hypothesis, we used miR microarrays to compare miR profiles of GBM cells with activated wild type EGFR (wtEGFR) and ΔEGFR, to cells with non-activated wtEGFR or kinase-dead ΔEGFR. miRs demonstrating differential expression were validated by northern blot analysis and qRT-PCR and potential pathways regulating miR expression were interrogated by pharmacological and genetic analysis. Candidate miR targets were validated by luciferase reporter assays and western blot analysis. The role of validated miRs and targets, in modulating ΔEGFR-mediated tumorgenicity, was analyzed by overexpression and knockdown studies in engineered glioma cell lines engrafted in athymic nude mice. Validated target significance was determined by survival-association expression analysis in a patient cohort of 67 newly diagnosed and 64 recurrent GBM cases. RESULTS: We observed and validated that ΔEGFR suppresses miR-9. The repression of miR-9 was due to the negative regulation of the primary miR-9 encoding transcript, pri-miR-9-2, by ΔEGFR. Downstream of ΔEGFR, the Ras/PI3K/AKT axis was required to suppress miR-9. We identified the transcription factor, FOXP1, to be a bona-fide miR-9 target. Upregulation of miR-9 decreased expression of FOXP1 in ΔEGFR cells, suggesting that miR-9 and FOXP1 may regulate, in part, ΔEGFR-dependent GBM growth. Consistent with this, miR-9 antagonized the tumor growth advantage conferred by ΔEGFR while FOXP1 knock-down inhibited the growth of ΔEGFR-driven tumors. Upregulation of FOXP1, as a consequence of inhibiting miR-9 activity, increased the tumorigenicity of GBM cells, suggesting that miR-9 is a tumor suppressor while FOXP1 likely functions as an oncogenic factor in GBM. Finally, high FOXP1 expression was significantly associated with poor survival in GBM patients, further supporting the notion that FOXP1 is an oncogenic factor. CONCLUSIONS: Collectively, these data reveal a novel regulatory mechanism by which ΔEGFR signaling through the Ras-PI3K-Akt pathway suppresses miR-9, resulting in FOXP1 expression and increased tumorigenicity. SECONDARY CATEGORY: n/a.

  • suppression of microRNA 9 by mutant egfr signaling upregulates foxp1 to enhance glioblastoma tumorigenicity
    Cancer Research, 2014
    Co-Authors: German Gomez, Stefano Volinia, Carlo M Croce, Ciro Zanca, Ryan J Emnett, David H Gutmann, Cameron Brennan, Frank B Furnari, Webster K Cavenee
    Abstract:

    These findings identify an important new mechanism through which a common EGFR mutant acts to drive advanced brain cancer.

  • suppression of microRNA 9 by mutant egfr signaling upregulates foxp1 to enhance glioblastoma tumorigenicity
    Cancer Research, 2014
    Co-Authors: German Gomez, Stefano Volinia, Carlo M Croce, Ciro Zanca, Ryan J Emnett, David H Gutmann, Cameron Brennan, Frank B Furnari, Webster K Cavenee
    Abstract:

    The EGF receptor (EGFR) is amplified and mutated in glioblastoma, in which its common mutation (ΔEGFR, also called EGFRvIII) has a variety of activities that promote growth and inhibit death, thereby conferring a strong tumor-enhancing effect. This range of activities suggested to us that ΔEGFR might exert its influence through pleiotropic effectors, and we hypothesized that microRNAs might serve such a function. Here, we report that ΔEGFR specifically suppresses one such microRNA, namely miR-9, through the Ras/PI3K/AKT axis that it is known to activate. Correspondingly, expression of miR-9 antagonizes the tumor growth advantage conferred by ΔEGFR. Silencing of FOXP1, a miR-9 target, inhibits ΔEGFR-dependent tumor growth and, conversely, de-repression of FOXP1, as a consequence of miR-9 inhibition, increases tumorigenicity. FOXP1 was sufficient to increase tumor growth in the absence of oncogenic ΔEGFR signaling. The significance of these findings is underscored by our finding that high FOXP1 expression predicts poor survival in a cohort of 131 patients with glioblastoma. Collectively, these data suggest a novel regulatory mechanism by which ΔEGFR suppression of miR-9 upregulates FOXP1 to increase tumorigenicity.

Olivier Tabary - One of the best experts on this subject based on the ideXlab platform.

  • microRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology
    Nature Communications, 2017
    Co-Authors: Florence Sonneville, Manon Ruffin, Christelle Coraux, Nathalie Rousselet, Philippe Le Rouzic, Sabine Blouquit-laye, Harriet Corvol, Olivier Tabary
    Abstract:

    Cystic fibrosis results from reduced cystic fibrosis transmembrane conductance regulator protein activity leading to defective epithelial ion transport. Ca2+-activated Cl- channels mediate physiological functions independently of cystic fibrosis transmembrane conductance regulator. Anoctamin 1 (ANO1/TMEM16A) was identified as the major Ca2+-activated Cl- channel in airway epithelial cells, and we recently demonstrated that downregulation of the anoctamin 1 channel in cystic fibrosis patients contributes to disease severity via an unknown mechanism. Here we show that microRNA-9 (miR-9) contributes to cystic fibrosis and downregulates anoctamin 1 by directly targeting its 3'UTR. We present a potential therapy based on blockage of miR-9 binding to the 3'UTR by using a microRNA target site blocker to increase anoctamin 1 activity and thus compensate for the cystic fibrosis transmembrane conductance regulator deficiency. The target site blocker is tested in in vitro and in mouse models of cystic fibrosis, and could be considered as an alternative strategy to treat cystic fibrosis.Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models.

  • microRNA-9 downregulates the ANO1 chloride channel and contributes to cystic fibrosis lung pathology
    Nature Publishing Group, 2017
    Co-Authors: Florence Sonneville, Manon Ruffin, Christelle Coraux, Nathalie Rousselet, Philippe Le Rouzic, Sabine Blouquit-laye, Harriet Corvol, Olivier Tabary
    Abstract:

    Downregulation of the anoctamin 1 calcium channel in airway epithelial cells contributes to pathology in cystic fibrosis. Here the authors show that microRNA-9 targets anoctamin 1 and that inhibiting this interaction improves mucus dynamics in mouse models

Jiangbo Zhang - One of the best experts on this subject based on the ideXlab platform.

  • down regulation of microRNA 9 leads to activation of il 6 jak stat3 pathway through directly targeting il 6 in hela cell
    Molecular Carcinogenesis, 2016
    Co-Authors: Jiangbo Zhang, Qing Xie, Junqiao Jia, Lijun Zhao, Xiangmei Chen, Jianliu Wang
    Abstract:

    microRNA-9 (miR-9) presents to exert distinct and even opposite functions in different kinds of tumors through targeting different cellular genes. However, its role in cervical adenocarcinoma remains uncertain. Here, we report that miR-9 is down-regulated in cervical adenocarcinoma due to its frequent promoter-hypermethylation and exerts its tumor suppressor role through inhibiting several novel target genes, including interleukin-6 (IL-6). The promoters of miR-9 precursors (mir-9-1, -2, and -3) were hypermethylated in cervical adenocarcinoma tissues. Demethylation treatment of HeLa dramatically increased the expression of mature miR-9. Both in vitro and in vivo functional experiments confirmed that miR-9 can inhibit the proliferation, migration, and malignant transformation abilities of HeLa cells. Bioinformatics methods and array-based RNA expression profiles were used to screen the downstream target genes of miR-9. Dual-luciferase reporting assay, real-time qPCR, and ELISA or Western blot confirmed four genes (CKAP2, HSPC159, IL-6, and TC10) to be novel direct target genes of miR-9. Pathway annotation analysis of the differently expressed genes (DEGs) induced by ectopic miR-9 expression revealed the enrichment in Jak/STAT3 pathway, which is one of the downstream pathways of IL-6. Ectopic expression of miR-9 in HeLa inhibited Jak/STAT3 signaling activity. Moreover, such effect could be partially reversed by the addition of exogenous IL-6. In conclusion, our results here present a tumor suppressor potential of miR-9 in cervical adenocarcinoma for the first time and suggest that miR-9 could repress tumorigenesis through inhibiting the activity of IL-6/Jak/STAT3 pathway.

  • comprehensive profiling of novel microRNA 9 targets and a tumor suppressor role of microRNA 9 via targeting igf2bp1 in hepatocellular carcinoma
    Oncotarget, 2015
    Co-Authors: Jiangbo Zhang, Jin Cheng, Zhenzhen Zeng, Yongfeng Wang, Qing Xie, Junqiao Jia, Ying Yan, Zhengyang Guo, Jian Gao, Mingjie Yao
    Abstract:

    microRNA-9 (miR-9) dysregulation is implicated in a variety of human malignancies including hepatocellular carcinoma (HCC), but its role remains contradictory. In this study, we explored the expression and methylation status of miR-9 in HCC samples, as well as the tumor-related functions of miR-9 in vitro. Bioinformatics analysis, array-based RNA expression profile, and literature retrieval were used to identify miR-9 targets in HCC. The potential downstream candidates were then validated by luciferase reporter assay, real-time quantitative PCR, and western blot or enzyme linked immunosorbent assay (ELISA). The expression status and clinicopathologic significances of miR-9 target genes in clinical samples were further explored. The results showed that miR-9 was frequently downregulated in primary HCC. Its silencing was largely contributed by a high frequency (42.5%) of mir-9-1 hypermethylation, which was correlated with bigger tumor size (P = 0.0234). In vitro functional studies revealed that miR-9 restoration retarded HCC cell proliferation and migration. IL-6, AP3B1, TC10, ONECUT2, IGF2BP1, MYO1D, and ANXA2 were confirmed to be miR-9 targets in HCC. Among them, ONECUT2, IGF2BP1, and ANXA2 were confirmed to be aberrantly upregulated in HCC. Moreover, upregulation of ONECUT2, IGF2BP1, and IL-6 were significantly associated with poor post-surgery prognosis (P = 0.0458, P = 0.0037 and P = 0.0461, respectively). Mechanically, miR-9 plays a tumor suppressive role partially through a functional miR-9/IGF2BP1/AKT&ERK axis. Our study suggests that miR-9 functions as a tumor suppressor in HCC progression by inhibiting a series of target genes, including the newly validated miR-9/IGF2BP1/AKT&ERK axis, thus providing potential therapeutic targets and novel prognostic biomarkers for HCC patients.

Nancy Papalopulu - One of the best experts on this subject based on the ideXlab platform.

  • microRNA 9 modulates hes1 ultradian oscillations by forming a double negative feedback loop
    Cell Reports, 2012
    Co-Authors: Boyan B. Bonev, P. Stanley, Nancy Papalopulu
    Abstract:

    Short-period (ultradian) oscillations of Hes1, a Notch signaling effector, are essential for maintaining neural progenitors in a proliferative state, while constitutive downregulation of Hes1 leads to neuronal differentiation. Hes1 oscillations are driven by autorepression, coupled with high instability of the protein and mRNA. It is unknown how Hes1 mRNA stability is controlled and furthermore, how cells exit oscillations in order to differentiate. Here, we identify a microRNA, miR-9, as a component of ultradian oscillations. We show that miR-9 controls the stability of Hes1 mRNA and that both miR-9 overexpression and lack of miR-9 dampens Hes1 oscillations. Reciprocally, Hes1 represses the transcription of miR-9, resulting in out-of-phase oscillations. However, unlike the primary transcript, mature miR-9 is very stable and thus accumulates over time. Given that raising miR-9 levels leads to dampening of oscillations, these findings provide support for a self-limiting mechanism whereby cells might terminate Hes1 oscillations and differentiate.

  • microRNA-9 regulates axon extension and branching by targeting Map1b in mouse cortical neurons
    Nature neuroscience, 2012
    Co-Authors: Federico Dajas-bailador, Boyan B. Bonev, Patricia P. Garcez, Peter Stanley, François Guillemot, Nancy Papalopulu
    Abstract:

    This paper reports that microRNA-9 controls axonal extension and branching of cortical neurons via its actions on the MAP1B protein.

  • microRNA-9 reveals regional diversity of neural progenitors along the anterior-posterior axis.
    Developmental cell, 2011
    Co-Authors: Boyan B. Bonev, Angela Oliveira Pisco, Nancy Papalopulu
    Abstract:

    Neural progenitors self-renew and generate neurons throughout the central nervous system. Here, we uncover an unexpected regional specificity in the properties of neural progenitor cells, revealed by the function of a microRNA--miR-9. miR-9 is expressed in neural progenitors, and its knockdown results in an inhibition of neurogenesis along the anterior-posterior axis. However, the underlying mechanism differs--in the hindbrain, progenitors fail to exit the cell cycle, whereas in the forebrain they undergo apoptosis, counteracting the proliferative effect. Among several targets, we functionally identify hairy1 as a primary target of miR-9, regulated at the mRNA level. hairy1 mediates the effects of miR-9 on proliferation, through Fgf8 signaling in the forebrain and Wnt signaling in the hindbrain, but affects apoptosis only in the forebrain, via the p53 pathway. Our findings show a positional difference in the responsiveness of progenitors to miR-9 depletion, revealing an underlying divergence of their properties.