Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

Peric, Delphine; Chvalova, K; Rousselet, Germain

doi:10.1038/onc.2011.391

Cited by 12 publications

(12 citation statements)

References 56 publications

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“…Of note, our findings also have implications in the context of tumors, as we show here that the ability to arrest cell cycle in response to disrupted miRNA synthesis is retained in tumor cells, irrespective of their p53 status. While this manuscript was in preparation, similar effects in tumor cell lines have been reported (Peric et al, 2012), in agreement with our work and in contrast to previous reports suggesting the opposite effect (Kumar et al, 2007). In summary, our data show that global miRNA disruption can trigger cellular senescence via deregulation of specific miRNAs and key cell-cycle regulators, highlighting the importance of miRNA-mediated regulation in the control of this tumor-suppressive response.…”

Section: Discussioncontrasting

confidence: 55%

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts

et al. 2013

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SummaryThe regulation of gene expression by microRNAs (miRNAs) is critical for normal development and physiology. Conversely, miRNA function is frequently impaired in cancer, and other pathologies, either by aberrant expression of individual miRNAs or dysregulation of miRNA synthesis. Here, we have investigated the impact of global disruption of miRNA biogenesis in primary fibroblasts of human or murine origin, through the knockdown of DGCR8, an essential mediator of the synthesis of canonical miRNAs. We find that the inactivation of DGCR8 in these cells results in a dramatic antiproliferative response, with the acquisition of a senescent phenotype. Senescence triggered by DGCR8 loss is accompanied by the upregulation of the cell-cycle inhibitor p21CIP1. We further show that a subset of senescence-associated miRNAs with the potential to target p21CIP1 is downregulated during DGCR8-mediated senescence. Interestingly, the antiproliferative response to miRNA biogenesis disruption is retained in human tumor cells, irrespective of p53 status. In summary, our results show that defective synthesis of canonical microRNAs results in cell-cycle arrest and cellular senescence in primary fibroblasts mediated by specific miRNAs, and thus identify global miRNA disruption as a novel senescence trigger.

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Section: Discussioncontrasting

confidence: 55%

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts

et al. 2013

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“…Thus, the abundance of miRNAs often does not change dramatically unless cells grow by proliferation or differentiation. Furthermore, the Drosha-cleavage step is coupled to cell growth in certain cell types (23). Finally, unprocessed pri-miRNAs seem to be degraded quickly via a pathway not well understood, and thus do not greatly accumulate.…”

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confidence: 99%

Processing of microRNA primary transcripts requires heme in mammalian cells

Weitz

Gong²,

Barr³

et al. 2014

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

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Significance MicroRNAs (miRNAs) have important functions in development and cell physiology. The vast majority of mature miRNAs are produced from primary transcripts of microRNAs (pri-miRNAs) by a multi-step pathway. The first step, cleavage of pri-miRNAs by the Microprocessor complex, is highly regulated but technically challenging to study. We have developed a robust method that faithfully measures pri-miRNA processing efficiency in live cells. Using this assay, we establish an essential function of heme in miRNA maturation, a provocative idea suggested by previous biochemical studies. Our study reveals a previously unknown cellular function of this central biological cofactor, linking metal ion biology with the regulation of noncoding RNAs. Our method should be widely useful for studying RNA processing in biology and diseases.

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“…Moreover, silencing DGCR8 in ovarian cancer cells attenuates two cellular survival pathways ERK1/2 and PI3K/AKT, indicating that DGCR8 functions as an oncogene in part by promoting cell growth. A recent study also showed that silencing DGCR8 and Drosha in breast cancer cells inhibited colony formation (18). …”

Section: Discussionmentioning

confidence: 99%

Silencing the Double-Stranded RNA Binding Protein DGCR8 Inhibits Ovarian Cancer Cell Proliferation, Migration, and Invasion

et al. 2013

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Purpose To evaluate the role of DiGeorge Critical Region 8 (DGCR8), a key component of miRNA biogenesis pathway in ovarian cancer. Methods The expression of DGCR8 in ovarian cancer was detected by immunostaining and DGCR8 knockdown in ovarian cancer cells was achieved using lentiviral shRNA. Differential expression of miRNAs was determined using Nanostring miRNA arrays and validated by real-time RT-PCR. Results DGCR8 was highly expressed in ovarian cancer. Knockdown of DGCR8 expression inhibits cell proliferation, migration, and invasion, as well as sensitizes cells to apoptosis induced by the chemotherapeutic drug cisplatin. Cellular survival pathways including ERK1/2 mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT were attenuated in DGCR8 knockdown cells. DGCR8 knockdown resulting in dysregulated miRNA gene expression. miR-27b was identified as the most highly down-regulated miRNA in DGCR8 knockdown cells and promoted cell proliferation in ovarian cancer cells. Conclusions DGCR8 functions as an oncogene in ovarian cancer, which is in part mediated by miR-27b.

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Identification of microprocessor-dependent cancer cells allows screening for growth-sustaining micro-RNAs

Cited by 12 publications

References 56 publications

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts

DGCR8-mediated disruption of miRNA biogenesis induces cellular senescence in primary fibroblasts

Processing of microRNA primary transcripts requires heme in mammalian cells

Silencing the Double-Stranded RNA Binding Protein DGCR8 Inhibits Ovarian Cancer Cell Proliferation, Migration, and Invasion

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