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Poliseno L, Salmena L, Riccardi L, Fornari A, Song MS, Hobbs RM, Sportoletti P, Varmeh S, Egia A, Fedele G, Rameh L, Loda M, Pandolfi PPIdentification of the miR-106b~25 microRNA cluster as a proto-oncogenic PTEN-targeting intron that cooperates with its host gene MCM7 in transformation. Sci Signal 3: ra29 Erratum in: Sci Signal. 2010;3(123):er6

Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215, USA.
Science Signaling (Impact Factor: 7.65). 04/2010; 3(117):ra29. DOI: 10.1126/scisignal.2000594
Source: PubMed

ABSTRACT PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor that antagonizes signaling through the phosphatidylinositol 3-kinase-Akt pathway. We have demonstrated that subtle decreases in PTEN abundance can have critical consequences for tumorigenesis. Here, we used a computational approach to identify miR-22, miR-25, and miR-302 as three PTEN-targeting microRNA (miRNA) families found within nine genomic loci. We showed that miR-22 and the miR-106b~25 cluster are aberrantly overexpressed in human prostate cancer, correlate with abundance of the miRNA processing enzyme DICER, and potentiate cellular transformation both in vitro and in vivo. We demonstrated that the intronic miR-106b~25 cluster cooperates with its host gene MCM7 in cellular transformation both in vitro and in vivo, so that the concomitant overexpression of MCM7 and the miRNA cluster triggers prostatic intraepithelial neoplasia in transgenic mice. Therefore, the MCM7 gene locus delivers two simultaneous oncogenic insults when amplified or overexpressed in human cancer. Thus, we have uncovered a proto-oncogenic miRNA-dependent network for PTEN regulation and defined the MCM7 locus as a critical factor in initiating prostate tumorigenesis.

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Available from: Massimo Loda, Aug 26, 2015
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    • "The two upregulated miR-HGs were SMC4 and MCM7 that are involved in DNA synthesis, mitosis and DNA repair (Hagstrom and Meyer, 2003; Lei and Tye, 2001), and contain two miRNA clusters in their introns: the miR-15bw16-2 and the miR-25w106b cluster, respectively. Both miRNA families have been described as being relevant to cancer (Bonci et al., 2008; Poliseno et al., 2010). Conversely, the six downregulated miR-HGs contain nine miRNAs whose relevance to cancer has not been investigated in detail: miR-548f-2, miR-1245, miR-218/ 218*, miR-342-3p/-5p, miR-483-3p/-5p and miR-1266 (Grady et al., 2008; Song et al., 2012; Soon et al., 2009; Tie et al., 2010; Veronese et al., 2010). "
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    ABSTRACT: Around 50% of all human microRNAs reside within introns of coding genes and are usually co-transcribed. Gene expression datasets, therefore, should contain a wealth of miRNA-relevant latent information, exploitable for many basic and translational research aims. The present study was undertaken to investigate this possibility. We developed an in silico approach to identify intronic-miRNAs relevant to breast cancer, using public gene expression datasets. This led to the identification of a miRNA signature for aggressive breast cancer, and to the characterization of novel roles of selected miRNAs in cancer-related biological phenotypes. Unexpectedly, in a number of cases, expression regulation of the intronic-miRNA was more relevant than the expression of their host gene. These results provide a proof of principle for the validity of our intronic miRNA mining strategy, which we envision can be applied not only to cancer research, but also to other biological and biomedical fields. Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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    • "Indeed, MEK blockade by PD0325901 inhibits CREB and GSK3 phosphorylation, potentially affecting both c-Jun transcription and protein stability (Lopez-Bergami et al., 2007; Wei et al., 2005). In addition to c-Jun modulation, MEK inhibition may regulate PTEN expression by selectively interfering with the expression of miR-25, that has recently been shown to finely regulate PTEN levels in human tumors and contribute to experimental tumorigenesis in vivo (Poliseno et al., 2010a). However, the activity status of signaling molecules connected to ERK1/2, and hence the crosstalk mechanisms that are operational in a specific cellular context, may differ among tissue types; thus, the role of PTEN in regulating ERK1/2 pathway and vice versa may differ among tumor types. "
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    ABSTRACT: Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a non-redundant lipid phosphatase that restrains and fine tunes the phosphatidylinositol-3-kinase (PI3K) signaling pathway. PTEN is involved in inherited syndromes, which predispose to different types of cancers and is among the most frequently inactivated tumor suppressor genes in sporadic cancers. Indeed, loss of PTEN function occurs in a wide spectrum of human cancers through a variety of mechanisms, including mutations, deletions, transcriptional silencing, or protein instability. PTEN prevents tumorigenesis through multiple mechanisms and regulates a plethora of cellular processes, including survival, proliferation, energy metabolism and cellular architecture. Moreover, recent studies have demonstrated that PTEN is able to exit, exist, and function outside the cell, allowing for inhibition of the PI3K pathway in neighboring cells in a paracrine fashion. Most recently, studies have shown that PTEN is also critical for stem cell maintenance and that PTEN loss can lead to the emergence and proliferation of cancer stem cell (CSC) clones. Depending on the cellular and tissue context of origin, PTEN deletion may result in increased self-renewal capacity or normal stem cell exhaustion and PTEN-defìcient stem and progenitor cells have been reported in prostate, lung, intestinal, and pancreatic tissues before tumor formation; moreover, reversible or irreversible PTEN loss is frequently observed in CSC from a variety of solid and hematologic malignancies, where it may contribute to the functional phenotype of CSC. In this review, we will focus on the role of PTEN expression and function and downstream pathway activation in cancer stem cell biology and regulation of the tumorigenic potential; the emerging role of PTEN in mediating the crosstalk between the PI3K and MAPK pathways will also be discussed, together with prospects for the therapeutic targeting of tumors lacking PTEN expression.
    Advances in Biological Regulation 09/2014; 56. DOI:10.1016/j.jbior.2014.07.002
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    • "Besides genetic inactivation, PTEN is targeted by several microRNAs (miRNAs) from the miR-106b-93-25 cluster known to be overexpressed in PCa (Figure 1). Overexpression of the miR cluster in prostate epithelium reduced PTEN expression and initiated prostate tumorigenesis in a transgenic mouse model (Poliseno et al., 2010a). Interestingly, the same set of miRNAs was shown to target PTENpg1, a pseudogene-derived RNA highly homologous to PTEN (Figure 1A). "
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