Interleukin-6–dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer

Löffler, Dennis; Brocke-Heidrich, Katja; Pfeifer, Gabriele; Stocsits, Claudia; Hackermüller, Jörg; Kretzschmar, A.; Burger, Renate; Gramatzki, Martin; Blumert, Conny; Bauer, Kay; Cvijic, Helena; Ullmann, Agnès; Stadler, Peter F.; Horn, Friedemann

doi:10.1182/blood-2007-03-081133

Cited by 580 publications

(582 citation statements)

References 26 publications

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“…Our finding that IFN-β also suppressed the expression of pri-miR-21 and pre-miR-21 suggests that it regulates miR-21 transcription. The putative regulatory region of the miR-21 gene is located within an intron of the overlapping transmembrane protein 49 (TMEM49) gene, and contains two consensus STAT3-binding sites at ∼800 bp upstream from the transcription start site (33). The results of a recent study (26), similar to our findings, showed that IFN-β induces the phosphorylation of STAT3 in glioma cells and thereby activates STAT3-mediated miR-21 transcription in a luciferase reporter gene system.…”

Section: Discussionsupporting

confidence: 80%

“…Loffler et al showed that IL-6-dependent STAT3 activates the transcription of miR-21 in multiple myeloma cells. Whereas IL-6 induces proliferation of myeloma cells, IFN-β reduces the growth of glioma cells or induces apoptosis in these cells (33). The possible explanation of this seemingly paradoxical role of STAT3 activation is that the STAT pathway is context-dependent and that various intracellular and/or environmental cues play a pivotal role in determining the outcome of pathway activation.…”

Section: Discussionmentioning

confidence: 98%

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The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

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Type I IFNs are involved in double-stranded RNA responses. Here, we investigated the possibility that IFN-β may induce or downregulate cellular microRNAs (miRNA) in human neoplasms and thereby use the RNA interference system to show antitumor effects. Because of its known connection to glioma biology, we focused on miR-21 among seven miRNAs influenced by IFN-β. We analyzed the effect of IFN-β treatment on miR-21 expression in glioma cells and intracranial glioma xenografts. IFN-β treatment reduced miR-21 expression in glioma cells markedly, and IFN-β administration suppressed the growth of glioma-initiating cell-derived intracranial tumors. The levels of primary miR-21 gene transcripts, precursor miR-21, and mature miR-21 decreased 6 hours after the addition of IFN-β, indicating that the reduction in miR-21 levels was due to transcriptional suppression. We did reporter assays to elucidate the IFN-β-mediated suppression of miR-21; the addition of signal transducers and activators of transcription 3 (STAT3)-expressing vectors induced the IFN-β-mediated suppression of miR-21, whereas STAT3-inhibiting agents inhibited the miR-21 suppression. Thus, the results of our study show that the downregulation of miR-21 contributes to the antitumor effects of IFN-β and that miR-21 expression is negatively regulated by STAT3 activation. These results highlight the importance of understanding the transcriptional regulation of the miRNAs involved in

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 98%

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

Ohno

Natsume

Kondo

et al. 2009

Molecular Cancer Research

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“…A highly relevant tumor-associated miRNA is miR-21, which is overexpressed in almost all tumors analysed so far (Volinia et al, 2006). The antiapoptotic role of miR-21, first described in glioblastoma (Chan et al, 2005), has been further characterized in cholangiocarcinoma (Meng et al, 2006) and multiple myeloma cells (Loffler et al, 2007). Moreover, miR-21 is implicated in breast cancer cell growth and invasiveness Zhu et al, 2008), in agreement with its detection in a subset of miRNAs highly correlating with biopathologic features of breast cancer .…”

Section: Introductionmentioning

confidence: 66%

“…Previously, two STAT3 sites, localized downstream to the AP-1 sites, have been implicated in the interleukin-6-mediated induction of miR-21, in multiple myeloma cells (Loffler et al, 2007). Remarkably, the induction of interleukin-6 has been recently involved in the mechanisms of RAS-dependent tumorigenesis in vivo (Ancrile et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

et al. 2008

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The transcription factor AP-1 plays key roles in tumorigenesis, by regulating a variety of protein-coding genes, implicated in multiple hallmarks of cancer. Among non-coding genes, no AP-1 target has been described yet in tumorigenesis. MicroRNAs (miRNAs) are negative post-transcriptional regulators of protein-coding genes. miRNA expression signatures are highly relevant in cancer and several tumor-associated miRNAs (oncomirs) play critical roles in oncogenesis. Here, we show that the miRNA miR-21, which represents the most frequently upregulated oncomir in solid tumors, is induced by AP-1 in response to RAS. By analyzing validated miR-21 targets, we have found that the tumor suppressors PTEN and PDCD4 are downregulated by RAS in an AP-1-and miR-21-dependent fashion. We further show that, given the role of PDCD4 as negative regulator of AP-1, the miR-21-mediated downregulation of PDCD4 is essential for the maximal induction of AP-1 activity in response to RAS. Our data reveal a novel mechanism of positive autoregulation of the AP-1 complex in RAS transformation and disclose the function of oncomirs as critical targets and regulators of AP-1 in tumorigenesis.

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“…The genomic locus encoding miR-21 is not amplified in most cancers, including those expressing very high levels of miR-21, such as glioblastoma and chronic lymphocytic leukemia, suggesting that the deregulated expression of this miRNA occurs at either the transcriptional or the post-transcriptional level or both. The transcription of miR-21 primary RNA is controlled by a conserved upstream enhancer, which has been demonstrated to be regulated by gp130-activated Stat3 in myeloma cells, and by AP-1 in promyelocitic differentiation induced by TPA (Lo¨ffler et al, 2007;Fujita et al, 2008). We have recently demonstrated that AP-1 activity is necessary, but not sufficient, for the induction of miR-21 triggered by Ras (Talotta et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

et al. 2010

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miR-21 is a microRNA (miRNA) frequently overexpressed in human cancers. Here we show that miR-21 is upregulated both in vitro and in vivo by oncogenic Ras, thus linking this miRNA to one of the most frequently activated oncogenes in human cancers. Ras regulation of miR-21 occurs with a delayed kinetic and requires at least two Ras downstream pathways. A screen of human thyroid cancers and non-small-cell lung cancers for the expression of miR-21 reveals that it is overexpressed mainly in anaplastic thyroid carcinomas, the most aggressive form of thyroid cancer, whereas in lung its overexpression appears to be inversely correlated with tumor progression. We also show that a LNA directed against miR-21 slows down tumor growth in mice. Consistently, a search for mRNAs downregulated by miR-21 shows an enrichment for mRNAs encoding cell cycle checkpoints regulators, suggesting an important role for miR-21 in oncogenic Ras-induced cell proliferation.

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Interleukin-6–dependent survival of multiple myeloma cells involves the Stat3-mediated induction of microRNA-21 through a highly conserved enhancer

Cited by 580 publications

References 26 publications

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

The Modulation of MicroRNAs by Type I IFN through the Activation of Signal Transducers and Activators of Transcription 3 in Human Glioma

An autoregulatory loop mediated by miR-21 and PDCD4 controls the AP-1 activity in RAS transformation

Upregulation of miR-21 by Ras in vivo and its role in tumor growth

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