Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells

Salati, Simona; Salvestrini, Valentina; Carretta, Chiara; Genovese, Elena; Rontauroli, Sebastiano; Zini, Roberta; Rossi, Chiara; Ruberti, Samantha; Bianchi, Elisa; Barbieri, Greta; Curti, Antonio; Castagnetti, Fausto; Gugliotta, Gabriele; Rosti, Gianantonio; Bergamaschi, Micaela; Tafuri, Agostino; Tagliafico, Enrico; Lemoli, Roberto M.; Manfredini, Rossella

doi:10.18632/oncotarget.17706

Cited by 45 publications

(35 citation statements)

References 37 publications

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“…In order to demonstrate whether SS cell behaviour was modulated by miR-494.3p through its potential target CXCR4, we transfected SW982 and SYO-I cell lines with miR-494-3p precursor. The significant decrease in CXCR4 expression was associated with a decrease in cell proliferation which was more evident in the SYO-I cells, that also responded with a significant increase in the apoptotic cell fraction in accordance with data on chronic myeloid leukemia and prostate cancer (16,26).…”

Section: Discussionsupporting

confidence: 89%

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

et al. 2018

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Synovial sarcoma (SS) is a rare tumour, with dismal survival when metastasis occurs. SS contains a characteristic translocation (X;18)(p11;q11) and the fusion genes appear to be mutually exclusive and concordant in primary and metastatic tumours. Novel prognostic and predictive factors are required. The C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor 4 (CXCR4) axis is involved in tumour development and metastatic spread in many types of cancer and previous data have demonstrated a pivotal role of CXCR4 in SS cell migration and invasion. Bioinformatics and biological data indicated CXCR4 is a possible candidate target of miR-494.3p, known to be involved in tumour progression. In this study, we analysed the expression of miR-494.3p and its potential target, CXCR4, in a series of SS specimens. A significantly lower miR-494.3p expression was found in the tumour compared to normal tissue associated with higher levels of CXCR4 both at the gene and protein level. The role of CXCR4 as a potential target of miR-494.3p was assessed in two SS cell lines (SW982 and SYO-I). Transfection with miR-494.3p expression plasmid led to a marked decrease in CXCR4 gene and protein expression, concomitant with a transitory decrease in cell proliferation and migration. The SYO-I cells also responded with an increased apoptotic fraction. The data of this study also demonstrate that the downregulation of miR-494.3p in SS surgical specimens, concomitant with an increased expression of its potential target, CXCR4, was more evident in the metastatic subset. In vitro experiments confirmed that miR-494.3p functioned as a tumour suppressor through the involvement of CXCR4 and ongoing studies are directed to better clarify its role in SS therapeutic strategies.

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Section: Discussionsupporting

confidence: 89%

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

et al. 2018

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“…CML usually progresses from the chronic phase (CP) to the accelerated phase (AP) and blast crisis (BC) with an accumulation of other cytogenetic abnormalities. It has been reported that the dysregulation of microRNAs (miRNAs) had an important impact on the initiation, progression and drug-resistance in CML [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

Zhang¹,

Jiang²,

Han³

et al. 2018

Oncotarget

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ABSTRACTmicroRNAs play important regulatory roles in hematologic malignancies, and dysregulation of circulating miRNAs serves as diagnostic, prognostic and predictive biomarkers in many diseases. The correlation of plasma miRNA profiles with the progression of chronic myeloid leukemia (CML) has not been investigated. We have applied microarrays to identify differentially expressed miRNAs, followed by qRT-PCR to validate candidate miRNAs from four sample pools including chronic phase (CP), accelerated phase(AP), blast crisis(BC) and healthy control. Clustering analyses revealed varying phase-specific patterns of plasma miRNA expression during CML progression. Different phases of CML showed differential expression profiles between sample pools during the progression. The functional annotation tool, DAVID, found that putative targets of dysregulated miRNAs in different phases of diease are involved in several important signaling pathways. Gradually decreased expression levels of miR-451a were validated in CML patients from the CP to AP and BC; when CML patients achieved major molecular response (MMR), miR-451a expression was increased and restored to normal range. These data provide an important resource for studies on CML progression and allow a better understanding of the fundamental differences in plasma miRNA expression profiles among the different phases of CML.

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“…MiR‐362‐5p is up‐regulated in fresh blood samples of CML cell lines and CML patients and is associated with growth arrest and DNA damage induced (GADD)‐45α down‐regulation and therefore can be used as a downregulator of GADD45α oncomiR, activating JNK1/2 and P38 signal transduction (Yang et al, ). Down‐regulation of miR‐494‐3p reduced TKI‐induced apoptosis, which indicated that miR‐494‐3p down‐regulation might contribute to the intrinsic TKI resistance of LSCs, and the result supports the development of novel therapies that target the regulation of miR‐494‐3p or its target to effectively eradicate LSCs (Salati et al, ). Overexpression and knockdown experiments of miR‐486‐3p demonstrated that miR‐486‐3p supported erythropoiesis while inhibiting megakaryocytopoiesis.…”

Section: Discussionmentioning

confidence: 78%

“…The three gene chips were from National Center of Biotechnology Information (NCBI) gene expression omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo). The three original microarray datasets included the expression profiles GSE90773 (Salati et al, ), GSE11889 (Bruns et al, ), GSE11675 (Lemoli et al, ), with 20 cases of CML patients. On a total of 36 matched CML patients with bone marrow LSCs and normal bone marrow HSCs, analysis was carried out using GEO2R, an online analysis tool for the GEO database that is based on R language.…”

Section: Introductionmentioning

confidence: 99%

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

Liu

Zhuang

et al. 2019

Molec Gen & Gen Med

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Background Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm that arises from the acquisition of constitutively active BCR‐ABL tyrosine kinase in hematopoietic stem cells. The persistence of bone marrow leukemia stem cells (LSCs) is the main cause of TKI resistance and CML relapse. Therefore, finding a key target or pathway to selectively target LSCs is of great significance for the thorough treatment of CML. Methods In this study, we aimed to identify key microRNAs, microRNA targets and pathways for the treatment of CML LSCs by integrating analyses of three microarray data profiles. We identified 51 differentially expressed microRNAs through integrated analysis of GSE90773 and performed functional gene predictions for microRNAs. Then, GSE11889 and GSE11675 were integrated to obtain differentially expressed genes (DEGs), and the overlapping DEGs were used as models to identify predictive functional genes. Finally, we identified 116 predictive functional genes. Clustering and significant enrichment analysis of 116 genes was based on function and signaling pathways. Subsequently, a protein interaction network was constructed, and module analysis and topology analysis were performed on the network. Results A total of 11 key candidate targets and 33 corresponding microRNAs were identified. The key pathways were mainly concentrated on the PI3K/AKT, Ras, JAK/STAT, FoxO and Notch signaling pathways. We also found that LSCs negatively regulated endogenous and exogenous apoptotic pathways to escape from apoptosis. Conclusion We identified key candidate targets and pathways for CML LSCs through bioinformatics methods, which improves our understanding of the molecular mechanisms of CML LSCs. These candidate genes and pathways may be therapeutic targets for CML LSCs.

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Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells

Cited by 45 publications

References 37 publications

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

miR‑494.3p expression in synovial sarcoma: Role of CXCR4 as a potential target gene

WITHDRAWN: Expression profiles and biological implications of plasma miRNAs associated with chronic myeloid leukemia phases

Identification of key candidate targets and pathways for the targeted treatment of leukemia stem cells of chronic myelogenous leukemia using bioinformatics analysis

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