A p53‐Dependent Tumor Suppressor Network Is Induced by Selective miR‐125a‐5p Inhibition in Multiple Myeloma Cells

Leotta, Marzia; Biamonte, Lavinia; Raimondi, Lavinia; Ronchetti, Domenica; Martino, Maria Teresa Di; Botta, Cirino; Leone, Emanuela; Pitari, Maria Rita; Neri, Antonino; Giordano, Antonio; Tagliaferri, Pierosandro; Tassone, Pierfrancesco; Amodio, Nicola

doi:10.1002/jcp.24669

Cited by 87 publications

(84 citation statements)

References 99 publications

(108 reference statements)

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“…For instance, forced expression of miR-125a-5p could reduce the expression of TP53 to enhance of NPC cell migration and invasion [31]. It could also down-regulate P53, which consequently promotes apoptosis and enhances cell growth and invasion in multiple myeloma cells [32]. It has also been reported that miR-125a-5p is a tumor suppressor in multiple cancers through directly inhibiting the expression of numerous genes like HDAC4, E2F3, Sirtuin7, p53, and TAZ [33][34][35][36][37].…”

Section: Discussionmentioning

confidence: 99%

miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion

Zhang¹,

Zhu²,

Li³

et al. 2015

ABBS

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Metastasis-associated gene 1 (MTA1) is associated with cell growth, metastasis, and survival in nonsmall-cell lung cancer (NSCLC). Several previous reports have demonstrated that microRNAs affect gene expression through interaction between their seed region and the 3′-untranslated region of the target mRNA, resulting in post-transcriptional regulation. The aim of this study was to identify miRNAs that suppress malignancy in NSCLC cells by targeting MTA1. Two human NSCLC cell lines were analyzed for the expression of MTA1 by quantitative RT-PCR and western blotting after transfection with MTA1 mimics. A luciferase reporter assay was established to test the direct connection between MTA1 and its upstream miRNAs. Cell proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, 5-ethynyl-2′-deoxyuridine analysis, and colony formation assay. Cell migration and invasive capacity were evaluated by wound-healing assay and transwell assay. The miRNA/MTA1 axis was also probed by quantitative RT-PCR and western blotting in samples from eight NSCLC patients. Among the candidate miRNAs, miR-125a-3p was shown to posttranscriptionally regulate MTA1 in NSCLC cells. These data were reinforced by the luciferase reporter assay, in addition to the demonstration that MTA1 is inversely correlated with miR-125a-3p in NSCLC tissues. Furthermore, miR-125a-3p was found to inhibit NSCLC cell proliferation, migration, and invasion, through the same mechanisms of down-regulated MTA1. Our report demonstrates that miR-125a-3p inhibits the proliferation, migration, and invasion of NSCLC cells through down-regulation of MTA1, indicating the role of the miR-125a-3p/MTA1 axis in NSCLC, and may provide novel insight into the molecular mechanisms underpinning the disease and potential therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion

Zhang¹,

Zhu²,

Li³

et al. 2015

ABBS

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“…MiR-125a is mapped to chromosome 19q13.41 and plays a crucial role in organ development of adult tissues [24,25]. Accumulating evidence has demonstrated that miR125a is functionally involved in the tumorigenesis of various types of cancers, including gastric cancer, breast cancer, and lung cancer, by regulating its target genes, which might be oncogenes or tumor suppressive genes [26][27][28][29][30][31][32].…”

Section: Discussionmentioning

confidence: 99%

MiR-125a Rs12976445 Polymorphism is Associated with the Apoptosis Status of Nucleus Pulposus Cells and the Risk of Intervertebral Disc Degeneration

Feng

Zang

et al. 2016

Cell Physiol Biochem

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Background: Spinal degenerative diseases are a major health problem and social burden worldwide. Intervertebral disc degeneration (IDD) is the pathological basis of spinal degenerative diseases and is characterized by loss of nucleus pulposus cells due to excessive apoptosis caused by various factors. MicroRNAs (miRNAs) have been reported to be functionally involved in the control of apoptosis. Methods: computational analysis and luciferase assay were used to identify the target of miR-125a, and cell culture, transfection were used to confirm such relationship. Sequencing was used to determine the genotype of each participant. Results: We confirmed the previous report that the presence of the minor allele (T) of rs12976445 polymorphism significantly downregulated the expression level of miR-125a in nucleus pulposus cells, leading to less efficient inhibition of its target gene. We also validated TP53INP1 as a target of miR-125a in nucleus pulposus cells using a dual luciferase reporter system, and the transfection of miR-125a significantly reduced the expression of TP53INP1. The expression level of TP53INP1 was significantly lower in nucleus pulposus cells genotyped as CT or TT than in those genotyped as CC, and the apoptosis rate was consistently lower in the CC group than in the nucleus pulposus cells collected from individuals carrying at least one minor allele of rs12976445 polymorphism. To study the association between rs12976445 polymorphism and the risk of IDD, we enrolled 242 patients diagnosed with IDD and 278 normal controls, and significant differences were noted regarding the genotype distribution of rs12976445 between the IDD and the control groups (OR = 2.69, 95% C.I. = 1.88-3.83, p < 0.0001). In summary, rs12976445 polymorphism is significantly associated with the risk of IDD in the Chinese population. Conclusion: The present study indicated that miR-125a is a promising potential target for patients with IDD in clinical practice.

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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

et al. 2016

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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); 1-12. Ó2016 AACR.

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A p53‐Dependent Tumor Suppressor Network Is Induced by Selective miR‐125a‐5p Inhibition in Multiple Myeloma Cells

Cited by 87 publications

References 99 publications

miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion

miR-125a-3p targets MTA1 to suppress NSCLC cell proliferation, migration, and invasion

MiR-125a Rs12976445 Polymorphism is Associated with the Apoptosis Status of Nucleus Pulposus Cells and the Risk of Intervertebral Disc Degeneration

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

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