Targeting miR-21 Inhibits<i>In Vitro</i>and<i>In Vivo</i>Multiple Myeloma Cell Growth

Leone, Emanuela; Morelli, Eugenio; Martino, Maria Teresa Di; Amodio, Nicola; Foresta, Umberto; Gullà, Annamaria; Rossi, Marco; Neri, Antonino; Giordano, Antonio; Munshi, Nikhil C.; Anderson, Kenneth C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

doi:10.1158/1078-0432.ccr-12-3325

Cited by 199 publications

(179 citation statements)

References 51 publications

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“…Its relevance in multiple myeloma was first suggested by Loffler and colleagues, who showed that miR-21 transcription is controlled by IL-6 through a mechanism involving STAT3, and that its ectopic expression gives independence from the IL-6-growth stimulus (33). More recently, we provided evidence that antagonism of miR-21 exerts antimultiple myeloma activity in vitro and in vivo (34). Importantly, miR-21 expression in multiple myeloma cells was significantly enhanced by the adherence of cells to human BM stromal cells (hBMSC), and anti-multiple myeloma activity of miR-21 inhibitors was exerted also in the context of BM milieu, antagonizing the protective role of BMSCs on multiple myeloma cells (34).…”

Section: Discussionmentioning

confidence: 53%

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Lionetti

Musto

Martino

et al. 2013

Clinical Cancer Research

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Purpose: Primary plasma cell leukemia (pPCL) is a rare and very aggressive form of plasma cell dyscrasia. To date, no information on microRNA (miRNA) expression in pPCL has been reported. This study aimed at investigating the involvement of miRNAs in pPCL and their possible relationship with higher tumor aggressiveness.Experimental design: Global miRNA expression profiles were analyzed in highly purified malignant plasma cells from 18 pPCL untreated patients included in a prospective clinical trial. MiRNA expression patterns were evaluated in comparison with a representative series of multiple myeloma patients, in relation to the most recurrent chromosomal abnormalities (as assessed by fluorescence in situ hybridization and single-nucleotide polymorphism-array analysis), and in association with clinical outcome. MiRNA expression was also integrated with gene expression profiles in pPCL and multiple myeloma samples.Results: We identified a series of deregulated miRNAs in pPCL (42 upregulated and 41 downregulated) in comparison with multiple myeloma. Some of them, on the basis of their reported functions and putative target genes computed by integrative analysis, might have a role in the pathobiology of pPCL. As regards chromosomal aberrations, the expression of some miRNAs mapped to hotspot altered regions was associated with DNA copy number of the corresponding loci. Finally, 4 miRNA (miR-497, miR-106b, miR-181a Ã , and miR-181b) were identified as having expression levels that correlated with treatment response, and 4 (miR-92a, miR-330-3p, miR-22, and miR-146a) with clinical outcome. Conclusions: Overall, our study provides insights into the possible contribution of miRNAs in the pathogenesis of pPCL and suggests targets for future therapeutic investigations.

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Section: Discussionmentioning

confidence: 53%

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Lionetti

Musto

Martino

et al. 2013

Clinical Cancer Research

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“…In addition, the tumor suppressor Spry2 was revealed to be negatively correlated with miR-21 expression in myeloma cells. Inhibition of miR-21 led to upregulation of PTEN and downregulation of phosphorylated AKT in xenografts of myeloma (47,48). These results suggested that miR-21 is important in hematological malignancies.…”

Section: Mir-21 and Hematological Malignanciesmentioning

confidence: 72%

Emerging role of microRNA-21 in cancer

2016

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Abstract. MicroRNAs (miRs) are a class of single-stranded RNA molecules of 15-27 nucleotides in length that regulate gene expression at the post-translational level. miR-21 is one of the earliest identified cancer-promoting 'oncomiRs', targeting numerous tumor suppressor genes associated with proliferation, apoptosis and invasion. The regulation of miR-21 and its role in carcinogenesis have been extensively investigated. Recent studies have focused on the diagnostic and prognostic value of miR-21 as well as its implication in the drug resistance of human malignancies. The further use of miR-21 as a biomarker and target for cancer treatments is likely to improve the outcome for patients with cancer. The present review highlights recent findings associated with the importance of miR-21 in hematological and non-hematological malignancies. IntroductionMicroRNAs (miRs) are a class of naturally occurring short non-coding RNA molecules of 15-27 nucleotides in length that regulate eukaryotic gene expression at the post-transcriptional level. Almost 2,000 human miRNAs have been identified through cloning and/or sequence analysis (1). They have key regulatory roles in the development, differentiation and apoptosis of normal cells, as well as in the determination of the final phenotype of cancer cells, affecting carcinogenesis and metastatic potential (2). miR-21 is an abundantly expressed miRNA in mammalian cells, whose upregulation is associated with numerous types of cancer (3,4). By generation of a conditional miR-21 knock-in mouse, it was demonstrated that miR-21 functions as an oncogene with its overexpression resulting in malignant B-cell lymphoma (5). Indeed, miR-21 was found to be the only consistently upregulated miRNA in a study that profiled 540 clinical samples from cancer patients (6). The majority of studies on miR-21 have focused on its role in carcinogenesis and its clinical application. miR-21 is also expressed in hematopoietic cells of the immune system, including B/T cells, monocytes, macrophages and dendritic cells. High miR-21 levels are, therefore, considered to be a marker of immune cell activation (7). Regarding pathological necrosis, miR-21 enhances cellular necrosis by negatively regulating tumor suppressor genes associated with the death receptor-mediated intrinsic apoptotic pathway (8). Biological function of miR-21The biological functions of various miRNAs, including miR-21, have been extensively investigated and miR-21 is

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“…In the last few years, a wealth of studies has shown deep dysregulation of miRNAs in human cancers, including multiple myeloma (3). Importantly, replacement of downregulated tumor suppressor (TS) miRNAs (4,5) or inhibition of oncogenic miRNAs (6)(7)(8) have demonstrated therapeutic value in multiple myeloma preclinical settings. A subclass of TSmiRNAs, named epi-miRNAs, is emerging as novel epigenetic regulators, which target and downregulate the expression of DNA methyltransferases (DNMT), histone deacetylases (HDAC), or components of the polycomb repressor complexes, thus representing relevant tools to revert epigenetic aberrations.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

Amodio

Stamato

Gullà

et al. 2016

Molecular Cancer Therapeutics

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Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma, and their effects can be efficiently counteracted by a class of tumor suppressor miRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDAC) in multiple myeloma, we investigated whether their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited multiple myeloma cell survival and migration and triggered apoptosis and autophagy, along with the induction of miR-29b expression by promoter hyperacetylation, leading to the downregulation of prosurvival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b, respectively, potentiated or antagonized SAHA activity on multiple myeloma cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human multiple myeloma. Altogether, our results shed light on a novel epigenetic circuitry regulating multiple myeloma cell growth and survival and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy. Mol Cancer Ther; 15(6); 1364-75. Ó2016 AACR.

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Targeting miR-21 InhibitsIn VitroandIn VivoMultiple Myeloma Cell Growth

Cited by 199 publications

References 51 publications

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

Emerging role of microRNA-21 in cancer

Therapeutic Targeting of miR-29b/HDAC4 Epigenetic Loop in Multiple Myeloma

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