MicroRNA–mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients

Bhise, Neha; Chauhan, Lata; Shin, Miyoung; Cao, Xueyuan; Pounds, Stanley; Lamba, Vishal; Lamba, Jatinder K.

doi:10.3389/fphar.2015.00324

Cited by 20 publications

(20 citation statements)

References 55 publications

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“…The expression of deactivating enzyme DCTD was found to be correlated with miR-24-3p expression (spearman r = −0.93; p-value < 0.01). Interestingly, in our previous study, we identified that expression of miRNA miR-24-3p was correlated with cytarabine-induced cell cytotoxicity (spearman r = −0.81, p -value < 0.05) [13] which is in agreement with the current observation. The expression of CMPK , a kinase responsible for phosphorylation of the monophosphate form of nucleoside analog was negatively correlated with the expression of miR-1301, miR-1323, miR-320e, miR-381, miR-507, miR-584-5p, miR-605, miR-762, miR-769-3p, miR-891a (all p -values < 0.01).…”

Section: Resultssupporting

confidence: 92%

MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

Bhise

Elsayed

Cao

et al. 2019

Genes

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Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient variation in expression levels of drug transporters or enzymes involved in their activation or inactivation of cytarabine and other analogs is a prime mechanism contributing to development of drug resistance. Since microRNAs (miRNAs) are known to regulate gene-expression, the aim of this study was to identify miRNAs involved in regulation of messenger RNA expression levels of cytarabine pathway genes. We evaluated miRNA and gene-expression levels of cytarabine metabolic pathway genes in 8 AML cell lines and The Cancer Genome Atlas (TCGA) data base. Using correlation analysis and functional validation experiments, our data demonstrates that miR-34a-5p and miR-24-3p regulate DCK, an enzyme involved in activation of cytarabine and DCDT, an enzyme involved in metabolic inactivation of cytarabine expression, respectively. Further our results from gel shift assays confirmed binding of these mRNA-miRNA pairs. Our results show miRNA mediated regulation of gene expression levels of nucleoside metabolic pathway genes can impact interindividual variation in expression levels which in turn may influence treatment outcomes.

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Section: Resultssupporting

confidence: 92%

MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

Bhise

Elsayed

Cao

et al. 2019

Genes

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“…7B; Table 5). Cancer-relevant examples include: Ptm1, which is a protein of unknown function that copurifies with late Golgi vesicles containing the v-SNARE, Tlg2p, but interestingly, its human homologs, TMEM87A and TMEM87B , were UES for cytarabine and identified in a study focused on cytarabine efficacy in acute myelogenous leukemia [281]. NAP1/NAP1L3/NAP1L4 , which is a nucleosome assembly protein involved in nuclear transport and exchange of histones H2A and H2B and also interacts with Clb2, is phosphorylated by CK2, and has protein abundance that increases in response to DNA replication stress [155].…”

Section: Resultsmentioning

confidence: 99%

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

Santos

Icyuz

Pound

et al. 2019

Preprint

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10Knowledge about synthetic lethality can be applied to enhance the efficacy of 11 anti-cancer therapies in individual patients harboring genetic alterations in their cancer 12 that specifically render it vulnerable. We investigated the potential for high-resolution 13 phenomic analysis in yeast to predict such genetic vulnerabilities by systematic, 14 comprehensive, and quantitative assessment of drug-gene interaction for gemcitabine 15 and cytarabine, substrates of deoxycytidine kinase that have similar molecular structures 16 yet distinct anti-tumor efficacy. Human deoxycytidine kinase (dCK) was conditionally 17 expressed in the S. cerevisiae genomic library of knockout and knockdown (YKO/KD) 18 strains, to globally and quantitatively characterize differential drug-gene interaction for 19 gemcitabine and cytarabine. Pathway enrichment analysis revealed that autophagy, 20 histone modification, chromatin remodeling, and apoptosis-related processes influence 21 gemcitabine specifically, while drug-gene interaction specific to cytarabine was less 22 enriched in Gene Ontology. Processes having influence over both drugs were DNA 23 repair and integrity checkpoints and vesicle transport and fusion. Non-GO-enriched 24 genes were also informative. Yeast phenomic and cancer cell line pharmacogenomics 25 data were integrated to identify yeast-human homologs with correlated differential gene 26 2 expression and drug-efficacy, thus providing a unique resource to predict whether 27 differential gene expression observed in cancer genetic profiles are causal in tumor-28 specific responses to cytotoxic agents. 29 30 Keywords: 31 yeast phenomics, gene-drug interaction, genetic buffering, quantitative high 32 throughput cell array phenotyping (Q-HTCP), cell proliferation parameters (CPPs), 33 gemcitabine, cytarabine, recursive expectation-maximization clustering (REMc), 34 pharmacogenomics 35 36 Introduction: 37Genomics has enabled targeted therapy aimed at cancer driver genes and 38 oncogenic addiction [1], yet traditional cytotoxic chemotherapeutic agents remain among 39 the most widely used and efficacious anti-cancer therapies [2]. Changes in the genetic 40 network underlying cancer can produce vulnerabilities to cytotoxic chemotherapy that 41 further influence the therapeutic window and provide additional insight into their 42 mechanisms of action [3,4]. A potential advantage of so-called synthetic lethality-based 43 treatment strategies is that they could have efficacy against passenger gene mutation or 44 compensatory gene expression, while classic targeted therapies are directed primarily at 45 driver genes ( Fig. 1A). Quantitative high throughput cell array phenotyping of the yeast 46 knockout and knockdown libraries provides a phenomic means for systems level, high- 47resolution modeling of gene interaction [5][6][7][8][9], which is applied here to predict cancer-48 relevant drug-gene interaction through integration with cancer pharmacogenomics 49 resources ( Fig. 1B). 50Nucleoside analogs include a diverse group of co...

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“…Huang et al found that miR-107 could directly combine with RAD51, and overexpression of miR-107 could significantly suppress the protein expression of RAD51 in various cancer cell lines [35]. Furthermore, previous studies have shown that in AML cells, multiple miRNAs including miR-107 were related to the apoptosis of AML tumor cells [36,37]. In this study, we found that miR-107 could directly target RAD51 and inhibit its expression, but unlike with RAD51, the expression of apoptosis-associated genes was up-regulated.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-107 promotes apoptosis of acute myelocytic leukemia cells by targeting RAD51

2021

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Introduction: This study aimed to investigate the role of microRNA (miRNA) that affects acute myelocytic leukemia (AML) and its potential molecular mechanism by constructing a miRNA-mRNA interaction network using bioinformatics methods. Material and methods: MicroRNA expression data of AML were retrieved from Gene Expression Omnibus (GEO) and analyzed by microarray analysis. Expression levels of miR-107 and RAD51 mRNA were detected by quantitative real time polymerase chain reaction (qRT-PCR). Protein expression of RAD51, pro-apoptotic protein Bax, apoptosis related protein CytC and anti-apoptotic protein Bcl-2 were determined by Western blot. The rate of cell apoptosis was detected by Annexin-V/PI. The predicted targeting relationship between miR-107 and the 3′UTR of RAD51 was first predicted by the online application TargetScan and then verified by dual-luciferase assay. Results: Acute myelocytic leukemia-associated genes (n = 197) and miRNAs (n = 1701) were retrieved from the database, the interaction network of miRNA-mRNA was constructed and the core position was occupied by RAD51. miR-107 exhibited a regulatory effect on RAD51 in which the mRNA and protein expression of RAD51 were both significantly inhibited by miR-107 mimics in vitro. Additionally, down-regulated expression of miR107 as well as up-regulated expression of RAD51 were detected not only in the plasma of AML patients compared to healthy volunteers, but also in AML cell lines compared to the normal bone marrow stromal cell line. Further study found that increased expression of miR-107 and the consequent down-regulation of RAD51 could aggravate the apoptosis of AML cells in vitro. Conclusions: Our present results showed that the crucial role of RAD51 and miR-107 in the apoptosis of AML cells, i.e., miR-107 promotes the apoptosis of AML cells through down-regulating the expression of RAD51.

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MicroRNA–mRNA Pairs Associated with Outcome in AML: From In Vitro Cell-Based Studies to AML Patients

Cited by 20 publications

References 55 publications

MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

A humanized yeast phenomic model of deoxycytidine kinase to predict genetic buffering of nucleoside analog cytotoxicity

MicroRNA-107 promotes apoptosis of acute myelocytic leukemia cells by targeting RAD51

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