The Janus-faced Nature of miR-22 in Hematopoiesis: Is It an Oncogenic Tumor Suppressor or Rather a Tumor-Suppressive Oncogene?

Wurm, Antje; Tenen, Daniel G.; Behre, Gerhard

doi:10.1371/journal.pgen.1006505

Cited by 12 publications

(11 citation statements)

References 16 publications

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“…The miRNAs have been recognized for many years to function either as tumor suppressors or as oncogenes that promote cancer progression. Certain miRNAs have dual roles, serving as both tumor suppressors and oncogenes in different tissues 33 , but a single miRNA never shows a dual role in the same cell line.…”

Section: Discussionmentioning

confidence: 99%

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

Wang

Filkowski

et al. 2018

Oncogenesis

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Antiestrogen resistance is a major challenge encountered during the treatment of estrogen receptor alpha positive (ERα+) breast cancer. A better understanding of signaling pathways and downstream transcription factors and their targets may identify key molecules that can overcome antiestrogen resistance in breast cancer. An aberrant expression of miR-22 has been demonstrated in breast cancer; however, its contribution to breast cancer resistance to fulvestrant, an antiestrogen drug, remains unknown. In this study, we demonstrated a moderate elevation in miR-22 expression in the 182R-6 fulvestrant-resistant breast cancer line we used as a model system, and this elevation was positively correlated with the expression of the miRNA biogenesis enzymes AGO2 and Dicer. The level of phosphorylated HER2/neu at Tyr877 was also upregulated in these cells, whereas the level of RelA/p65 phosphorylated at Ser536 (p-p65) was downregulated. Knockdown of HER2/neu led to an induction of p-p65 and a reduction in miR-22 levels. Luciferase assays identified two NF-κB binding motifs in the miR-22 promoter that contributed to transcriptional repression of miR-22. Activation of RelA/p65, triggered by LPS, attenuated miR-22 expression, but this expression was restored by sc-514, a selective IKKβ inhibitor. Inhibition of miR-22 suppressed cell proliferation, induced apoptosis and caused cell cycle S-phase arrest, whereas enhancing expression of p21Cip1/Waf1 and p27Kip1. Surprisingly, ectopic expression of miR-22 also suppressed cell proliferation, induced apoptosis, caused S-phase arrest, and promoted the expression of p21Cip1/Waf1 and p27Kip1. Ectopic overexpression of miR-22 repressed the expression of FOXP1 and HDAC4, leading to a marked induction of acetylation of HDAC4 target histones. Conversely, inhibition of miR-22 promoted the expression of both FOXP1 and HDAC4, without the expected attenuation of histone acetylation. Instead, p53 acetylation at lysine 382 was unexpectedly upregulated. Taken together, our findings demonstrated, for the first time, that HER2 activation dephosphorylates RelA/p65 at Ser536. This dephosphoryalted p65 may be pivotal in transactivation of miR-22. Both increased and decreased miR-22 expression cause resensitization of fulvestrant-resistant breast cancer cells to fulvestrant. HER2/NF-κB (p65)/miR-22/HDAC4/p21 and HER2/NF-κB (p65)/miR-22/Ac-p53/p21 signaling circuits may therefore confer this dual role on miR-22 through constitutive transactivation of p21.

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Section: Discussionmentioning

confidence: 99%

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

Wang

Filkowski

et al. 2018

Oncogenesis

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“…32 Conflicting roles for miR-22 have been reported in the development of hematopoietic malignancies, as a tumor suppressor 45 or oncogenic. 46,47 Most recently, Weiss and Ito reported that miR-22 is upregulated during in vivo murine megakaryopoiesis, and that miR-22 knockout impairs megakaryocytic differentiation, while miR-22 overexpression promotes megakaryocytic differentiation in the K562 cell line. 48 Their results suggest a similar miR-22 role as we report here ( Figure 2D).…”

Section: -5p Inducesmentioning

confidence: 99%

Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin’s impact on hematopoietic stem & progenitor cells

Kao

Jiang

Papoutsakis

2020

Preprint

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Word Count (Text): 5429 Word Count (Abstract): 246 Figure Count: 7Table Count: 2 Reference Count: 61 Key Points• miR-486-5p and miR-22-3p drive megakaryocytic differentiation in the absence of thrombopoietin.• Megakaryocytic microparticles trigger megakaryocytic differentiation of CD34 + cells through JNK and PI3K/Akt/mTOR signaling. AbstractMegakaryocytes shed and release submicron size microparticles (MkMPs), the most abundant microparticle in circulation. We have previously reported that MkMPs target peripheral-blood CD34 + hematopoietic stem/progenitor cells (HSPCs) to induce megakaryocytic differentiation and proliferation, and that small RNAs delivered to HSPCs via MkMPs play an important role in the development of this phenotype. Here, using single-molecule real-time (SMRT) RNA sequencing (RNAseq), we identify the top seven most abundant microRNAs (miRs) in MkMPs as potential candidates in mediating the effect of MkMPs on HSPCs. Using miR mimics, we demonstrate that among the seven most abundant miRs, two, miR-486-5p and miR-22-3p, are able to drive the Mk differentiation of HSPCs in the absence of thrombopoietin (TPO). The effect of these two miRs is comparable to the TPO-or MkMP-induced megakaryocytic differentiation of HSPCs, thus suggesting that these two miRs are responsible for this MkMPinduced phenotype. To probe the signaling through which MkMPs might enable this phenotype, we used kinase inhibitors of potential signaling pathways engaged in megakaryocytic differentiation. Our data suggest that MkMP-induced Mk differentiation of HSPCs is enabled through JNK and PI3K/Akt/mTOR signaling. Our data show that MkMPs activate Akt and mTOR phosphorylation. Furthermore, MkMPs downregulate PTEN expression, a direct target of miR-486-5p and a negative regulator of PI3K/Akt signaling, via JNK signaling. Taken together, our data provide a mechanistic understanding of the biological effect of MkMPs in inducing megakaryocytic differentiation of HSPCs, which, as was previously suggested, is a phenotype of potential physiological significance in stress megakaryopoiesis.

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“…For example, miR-22, which is downregulated in some lung cancer specimens, has been shown to repress the receptor tyrosine kinase, ERBB3 (Ling et al, 2012), and reduced expression of miR-22 is associated with poor prognosis in colorectal cancer (Zhang et al, 2012). More recently, the miR-22’s role in the hematopoietic system has also grown more complex (Wurm et al, 2017). Two studies have explored a role for miR-22 in promoting myeloid differentiation and serving as a tumor suppressor in de novo AML through the repression of known oncogenic pathways (Jiang et al, 2016; Shen et al, 2016).…”

Section: Micrornas In Hematologic Malignanciesmentioning

confidence: 99%

A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease

Weiss¹,

Ito²

2017

International Review of Cell and Molecular Biology

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MicroRNAs (miRNAs) are a class of endogenously encoded ~22 nucleotide, noncoding, single-stranded RNAs that contribute to development, body planning, stem cell differentiation, and tissue identity through posttranscriptional regulation and degradation of transcripts. Given their importance, it is predictable that dysregulation of miRNAs, which target a wide variety of transcripts, can result in malignant transformation. In this review, we explore the discovery of miRNAs, their mechanism of action, and the tools that aid in their discovery and study. Strikingly, many of the studies that have expanded our understanding of the contributions of miRNAs to normal physiology and in the development of diseases have come from studies in the hematopoietic system and hematologic malignancies, with some of the earliest identified functions for mammalian miRNAs coming from observations made in leukemias. So, with a special focus on the hematologic system, we will discuss how miRNAs contribute to differentiation of stem cells and how dysregulation of miRNAs contributes to the development of malignancy, by providing examples of specific miRNAs that function as oncogenes or tumor suppressors, as well as of defects in miRNA processing. Finally, we will discuss the promise of miRNA-based therapeutics and challenges for the future study of disease-causing miRNAs.

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The Janus-faced Nature of miR-22 in Hematopoiesis: Is It an Oncogenic Tumor Suppressor or Rather a Tumor-Suppressive Oncogene?

Cited by 12 publications

References 16 publications

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

A dual role of miR-22 modulated by RelA/p65 in resensitizing fulvestrant-resistant breast cancer cells to fulvestrant by targeting FOXP1 and HDAC4 and constitutive acetylation of p53 at Lys382

Combinatorial effect of miR-486-5p & miR-22-3p mimics thrombopoietin’s impact on hematopoietic stem & progenitor cells

A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease

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