Modulation of Cellular Migration and Survival by c-Myc through the Downregulation of Urokinase (uPA) and uPA Receptor

Alfano, Daniela; Votta, Giuseppina; Schulze, Almut; Downward, Julian; Caputi, M; Stoppelli, Maria Patrizia; Iaccarino, Ingram

doi:10.1128/mcb.01442-09

Cited by 26 publications

(49 citation statements)

References 43 publications

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“…Therefore, we propose that MIR17HG-miRNAs play a role in sustaining MYC-driven proliferative state by targeting genes/pathways involved in EMT, a process that can be activated by a various types of stress through TGFB activation and is intrinsically linked to MYC inactivation and cell growth arrest. This is in line with previous observations that MYC suppresses cell invasive migration and tumor metastasis, whereas TGFB and hypoxia inactivate MYC [48, 49], Taken together, these findings implicate a regulatory network, composed of MYC, MIR17HG, and TGFB pathway, in governing cell phenotypic switch between proliferative and mesenchymal states (Fig. 8c).…”

Section: Discussionsupporting

confidence: 92%

Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer

Fan

Sethuraman

Brown

et al. 2014

Breast Cancer Res Treat

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The purpose of this study is to identify metastasis- associated genes/signaling pathways in basal-like breast tumors. Kaplan–Meier analysis of two public meta-datasets and functional classification was used to identify genes/signaling pathways significantly associated with distant metastasis free survival. Integrated analysis of expression correlation and interaction between mRNAs and miRNAs was used to identify miRNAs that potentially regulate the expression of metastasis-associated genes. The novel metastatic suppressive role of miR-17-5p was examined by in vitro and in vivo experiments. Over 4,000 genes previously linked to breast tumor progression were examined, leading to identification of 61 and 69 genes significantly associated with shorter and longer DMFS intervals of patients with basal-like tumors, respectively. Functional annotation linked most of the pro-metastatic genes to epithelial mesenchymal transition (EMT) process and three intertwining EMT-driving pathways (hypoxia, TGFB and Wnt), whereas most of the anti-metastatic genes to interferon signaling pathway. Members of three miRNA families (i.e., miR-17, miR-200 and miR-96) were identified as potential regulators of the pro-metastatic genes. The novel anti-metastatic function of miR-17-5p was confirmed by in vitro and in vivo experiments. We demonstrated that miR-17-5p inhibition in breast cancer cells enhanced expression of multiple pro-metastatic genes, rendered cells metastatic properties, and accelerated lung metastasis from orthotopic xenografts. In contrast, intratumoral administration of miR-17-5p mimic significantly reduced lung metastasis. These results provide evidence supporting that EMT activation and IFN pathway inactivation are markers of metastatic progression of basal-like tumors, and members of miR-17, miR-200, and miR-96 families play a role in suppressing EMT and metastasis. The metastasis-associated genes identified in this study have potential prognostic values and functional implications, thus, can be exploited as therapeutic targets to prevent metastasis of basal-like breast tumors.

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Section: Discussionsupporting

confidence: 92%

Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer

Fan

Sethuraman

Brown

et al. 2014

Breast Cancer Res Treat

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“…With the aim of identifying MYC-regulated lncRNAs that could play a driving role in lymphoma development, we set up a bioinformatic pipeline to screen for lncRNAs differentially regulated in MYCinducible model cell lines and a set of BL samples. In particular, we used RNA-seq data obtained from (i) hT-RPE-MycER cells, an immortalized retinal pigment epithelial cell line expressing the MycER fusion protein (a cell line shown to be a relevant tool for the study of several aspects of MYC activity in oncogenic transformation) (38,39); (ii) P493-6 cells, an immortalized B-lymphoblastic cell line carrying a tetracyclin-inducible MYC construct that was shown to be a good model to study MYC-induced lymphomas (40,41); and (iii) 91 GC B cell-derived lymphoma samples subjected to RNA-seq in the framework of the International Cancer Genome Consortium project on malignant lymphoma [ICGC MMML-Seq (International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing)], including 16 BLs, 35 DLBCLs, 40 FLs, and 4 controls (normal GC B-cell samples) (Table S1). …”

Section: Resultsmentioning

confidence: 99%

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Doose¹,

Haake

Bernhart³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite the established role of the transcription factor MYC in cancer, little is known about the impact of a new class of transcriptional regulators, the long noncoding RNAs (lncRNAs), on MYC ability to influence the cellular transcriptome. Here, we have intersected RNA-sequencing data from two MYC-inducible cell lines and a cohort of 91 B-cell lymphomas with or without genetic variants resulting in MYC overexpression. We identified 13 lncRNAs differentially expressed in IG-MYC-positive Burkitt lymphoma and regulated in the same direction by MYC in the model cell lines. Among them, we focused on a lncRNA that we named MYC-induced long noncoding RNA (MINCR), showing a strong correlation with MYC expression in MYC-positive lymphomas. To understand its cellular role, we performed RNAi and found that MINCR knockdown is associated with an impairment in cell cycle progression. Differential gene expression analysis after RNAi showed a significant enrichment of cell cycle genes among the genes down-regulated after MINCR knockdown. Interestingly, these genes are enriched in MYC binding sites in their promoters, suggesting that MINCR acts as a modulator of the MYC transcriptional program. Accordingly, MINCR knockdown was associated with a reduction in MYC binding to the promoters of selected cell cycle genes. Finally, we show that down-regulation of Aurora kinases A and B and chromatin licensing and DNA replication factor 1 may explain the reduction in cellular proliferation observed on MINCR knockdown. We, therefore, suggest that MINCR is a newly identified player in the MYC transcriptional network able to control the expression of cell cycle genes.MYC | lncRNA | cell cycle | B-cell lymphoma M YC is a transcription factor belonging to the basic helixloop-helix zipper family that was originally identified in Burkitt lymphoma (BL) because of a chromosomal translocation that juxtaposes the MYC oncogene with one of three immunoglobulin (Ig) loci (1-3). In BL, the deregulation of the oncogenic transcription factor MYC is considered to be the major driving force in lymphoma development (4, 5). MYC overexpression is not restricted to BL and has been found to be a common feature SignificanceGains of the MYC gene are the most common imbalances in cancer and are associated with poor prognosis, particularly in B-cell lymphoma. Recent advances in DNA sequencing have revealed the existence of thousands of long noncoding RNAs (lncRNAs) with unknown functional relevance. We have here identified a MYC-regulated lncRNA that we named MYC-induced long noncoding RNA (MINCR) that has a strong correlation with MYC expression in cancer. We show that MINCR is functional and controls cell cycle progression by influencing the expression of MYC-regulated cell cycle genes. MINCR is, therefore, a novel player in MYC's transcriptional network, with the potential to open new therapeutic windows in the fight against malignant lymphoma and, possibly, all cancers that rely on MYC expression.

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“…We selected siRNA sequence as reported by Alfano et al [7]. One siRNA targeting SD rat c-myc gene and one scrambled siRNA with the following sense and antisense sequences were synthesized:…”

Section: Synthesis Of C-myc Sirnamentioning

confidence: 99%

Small Interfering RNA to c-myc Inhibits Vein Graft Restenosis in a Rat Vein Graft Model

Wang

Liu

Shen

et al. 2011

Journal of Surgical Research

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Modulation of Cellular Migration and Survival by c-Myc through the Downregulation of Urokinase (uPA) and uPA Receptor

Cited by 26 publications

References 43 publications

Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer

Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer

MINCR is a MYC-induced lncRNA able to modulate MYC’s transcriptional network in Burkitt lymphoma cells

Small Interfering RNA to c-myc Inhibits Vein Graft Restenosis in a Rat Vein Graft Model

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