Both miR-17-5p and miR-20a Alleviate Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating STAT3 Expression

Zhang, Miaomiao; Liu, Qiaofei; Mi, Siping; Li, Xue; Zhang, Zhiqian; Su, Xiaomin; Liu, Jinyi; Chen, Yingying; Wang, Mengmeng; Zhang, Yuan; Guo, Fuyu; Zhang, Zhujun; Yang, Rongcun

doi:10.4049/jimmunol.1002989

Cited by 150 publications

(131 citation statements)

References 39 publications

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“…[35][36][37] STAT3 has also been found to be a target of miR-17 and miR-20a in mouse ES cells and mouse myeloid-derived suppressor cells. 38,39 Here, we show that miR-17 and miR-20a can target the p21 and STAT3 3 0 UTR to inhibit the expression of p21 and STAT3 in human cells. STAT3 exists in two isoforms, STAT3a and STAT3b, and they share a similar 3 0 UTR sequences.…”

Section: Discussionmentioning

confidence: 74%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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Hypoxia-inducible factor 1 (HIF-1) is a crucial transcription factor for the cellular adaptive response to hypoxia, which contributes to multiple events in cancer biology. MicroRNAs (miRNAs) are involved in almost all cellular activities such as differentiation, proliferation, and apoptosis. In this work, we use miRNA microarrays to profile miRNA expression in acute myeloid leukemia (AML) cells with inducible HIF-1a expression, and identify 19 differentially expressed miRNAs. Our study shows that HIF-1a represses the expression of miR-17 and miR-20a by downregulating c-Myc expression. These two miRNAs alleviate hypoxia and HIF-1a-induced differentiation of AML cells. More intriguingly, miR-17 and miR-20a directly inhibit the p21 and STAT3 (signal transducer and activator of transcription 3) expression, both of which can reverse miR-17/miR-20a-mediated abrogation of HIF-1a-induced differentiation. Moreover, we show in vivo that miR-20a contributes to HIF-1a-induced differentiation of leukemic cells. Taken together, our results suggest that HIF-1a regulates the miRNA network to interfere with AML cell differentiation, representing a novel molecular mechanism for HIF-1-mediated anti-leukemic action. Hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcriptional factor that consists of the oxygen-sensitive alpha subunit (HIF-1a) and the constitutively expressed beta subunit (HIF-1b), is a master regulator for the cellular adaptive response to oxygen concentration. 1 Under normoxic conditions, proline residues 402 and 564 of the HIF-1a protein are hydroxylated by specific prolyl hydroxylases (PHDs) that utilize O 2 and a-ketoglutarate as co-factors. The hydroxylated HIF-1a protein is subject to ubiquitination by the E3 ubiquitin ligase von Hippel-Lindau (VHL), which leads to its degradation. In contrast, hypoxic conditions cause the accumulation of HIF-1a protein by inhibiting its hydroxylation, and subsequent ubiquitination and degradation. 2 The stabilized HIF-1a protein translocates into the nucleus, where it forms a heterodimer with HIF-1b and modulates the expression of hundreds of genes through binding to hypoxia-responsive elements (HREs; 5 0 -RCGTG-3 0 ) on their promoters. These HIF-1-targeted genes help the cell adapt to hypoxia by influencing processes such as erythropoiesis, angiogenesis, cell metabolism, growth, apoptosis, and differentiation.Intriguingly, HIF-1a has been shown to contribute to the pathogenesis and progression of multiple kinds of diseases, including cancer. 1,3 Although a hypoxic microenvironment is regarded as a hallmark of solid tumors, and hypoxia-stabilized HIF-1a protein contributes to tumor growth, angiogenesis, and metastasis, 4 several groups, including our own, have reported that HIF-1a protein can trigger acute myeloid leukemia (AML) cells to undergo differentiation through a transcription-independent mechanism, inhibiting the progression of AML. [5][6][7][8][9] MicroRNAs (miRNAs) are a distinct class of small noncoding RNAs of around 22 nucleotides in length that posttra...

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Section: Discussionmentioning

confidence: 74%

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

et al. 2012

Cell Death Differ

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“…It has been reported that miRNAs, including miR-17-5p, miR-20a (30), miR-223 (31), and miR-494 (32), are involved in regulating the differentiation and function of tumor-expanded MDSCs. miR-17-5p and miR-20a alleviate the immunosuppressive potential of MDSCs by modulating STAT3 expression (30). Additionally, miR-223 suppresses differentiation of tumor-induced MDSCs from bone marrow cells via targeting MEF2C.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-9 Regulates the Differentiation and Function of Myeloid-Derived Suppressor Cells via Targeting Runx1

Tian

Rui

Tang

et al. 2015

The Journal of Immunology

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Myeloid-derived suppressor cells (MDSCs) play a critical role in tumor-associated immunosuppression, thus affecting effective immunotherapies for cancers. However, the molecular mechanisms involved in regulating the differentiation and function of MDSCs remain largely unclear. In this study, we found that inhibition of microRNA (miR)-9 promoted the differentiation of MDSCs with significantly reduced immunosuppressive function whereas overexpression of miR-9 markedly enhanced the function of MDSCs. Notably, knockdown of miR-9 significantly impaired the activity of MDSCs and inhibited the tumor growth of Lewis lung carcinoma in mice. Moreover, miR-9 regulated MDSCs differentiation by targeting the runt-related transcription factor 1, an essential transcription factor in regulating MDSC differentiation and function. Furthermore, the CREB was found to regulate miR-9 expression in MDSCs. Taken together, our findings have identified a critical role of miR-9 in regulating the differentiation and function of MDSCs.

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“…miR-17-5p and miR-20a are expressed at low levels in myeloid-derived suppresser cells and alleviate the suppressive function of myeloid-derived suppresser cells by targeting the transcription factor STAT3. 85 Peroxisome proliferatoractivated receptor c (PPARc) expression is reduced after LPS stimulation due to miR-27b induction, which directly targets PPARc mRNA. 63 Inhibition of miR-27b increased PPARc expression and thus resulted in the reduced production of pro-inflammatory cytokines from LPS-stimulated macrophages.…”

Section: Mirnas In Regulation Of Tlr and Rig-i Pathways Yk LI And Xy mentioning

confidence: 99%

MicroRNAs in the regulation of TLR and RIG-I pathways

2012

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The innate immune system recognizes invading pathogens through germline-encoded pattern recognition receptors (PRRs), which elicit innate antimicrobial and inflammatory responses and initiate adaptive immunity to control or eliminate infection. Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I) are the key innate immune PRRs and are tightly regulated by elaborate mechanisms to ensure a beneficial outcome in response to foreign invaders. Although much of the focus in the literature has been on the study of protein regulators of inflammation, microRNAs (miRNAs) have emerged as important controllers of certain features of the inflammatory process. Several miRNAs are induced by TLR and RIG-I activation in myeloid cells and act as feedback regulators of TLR and RIG-I signaling. In this review, we comprehensively discuss the recent understanding of how miRNA networks respond to TLR and RIG-I signaling and their role in the initiation and termination of inflammatory responses. Increasing evidence also indicates that both virus-encoded miRNAs and cellular miRNAs have important functions in viral replication and host anti-viral immunity.

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Both miR-17-5p and miR-20a Alleviate Suppressive Potential of Myeloid-Derived Suppressor Cells by Modulating STAT3 Expression

Cited by 150 publications

References 39 publications

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

HIF-1α downregulates miR-17/20a directly targeting p21 and STAT3: a role in myeloid leukemic cell differentiation

MicroRNA-9 Regulates the Differentiation and Function of Myeloid-Derived Suppressor Cells via Targeting Runx1

MicroRNAs in the regulation of TLR and RIG-I pathways

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