Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo

Morelli, Eugenio; Leone, Emanuela; Cantafio, Maria Eugenia Gallo; Martino, Maria Teresa Di; Amodio, Nicola; Biamonte, Lavinia; Gullà, Annamaria; Foresta, Umberto; Pitari, Maria Rita; Botta, Cirino; Rossi, Marco; Neri, Antonino; Munshi, Nikhil C.; Anderson, Kenneth C.; Tagliaferri, Pierosandro; Tassone, Pierfrancesco

doi:10.1038/leu.2015.124

Cited by 104 publications

(92 citation statements)

References 52 publications

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“…We then validated the elevated levels of five of those (miR-125b-5p, miR-4326, miR-4498, miR-490-3p and miR-7155-5p) in a second clinical study. Most of the targets of these miRNAs are cancer-associated genes such as APC2, IGF2, and IRF4 (15)(16)(17) that are involved in cell proliferation, cell cycle, apoptosis, invasion and metastasis. Fur ther more, ROC analysis demonstrated that miR-125b-5p and miR-490-3p were accurate in distinguishing MM patients from healthy subjects, resulting in AUCs of 0.954 (sensitivity=86%, specificity=96%, 95% CI 0.901-1.006, P<0.001) and 0.866 (sensitivity=60%, specificity=85%, 95% CI 0.522-0.836, P= 0.028), respectively.…”

Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

et al. 2018

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Abstract. Aberrant expression of microRNAs (miRNAs) contributes to the progression and outcomes of several types of tumor, while circulating miRNAs have been reported to act as biomarkers for several types of cancer. To identify specific circulating miRNAs associated with multiple myeloma (MM), a miRNA microarray analysis was used, which identified 8 upregulated miRNAs and 4 downregulated miRNAs in the plasma of 6 patients with MM compared with 6 healthy individuals. Based on the microarray results, the 8 miRNAs (miR-125b-5p, miR-483-3p, miR-4326, miR-6894-3p, miR-4498, miR-490-3p, miR-7155-5p and miR-937-3p), which were notably upregulated in MM patients were chosen for a second clinical study in 20 healthy controls and 35 patients with MM using reverse transcription-quantitative polymerase chain reaction. Receiver operating characteristic analysis demonstrated that miR-125b-5p and miR-490-3p displayed considerable diagnostic accuracy for MM with areas under the curve of 0.954 (P<0.001) and 0.866 (P=0.028), respectively. In addition, the plasma level of miR-125b-5p was associated with the international staging system disease stage. Patients with higher levels of plasma miR-125b-5p had a significantly shorter event-free survival. However, miR-490-3p levels were not associated with event-free survival (P>0.05). In summary, miR-125b-5p may serve as a potential clinical biomarker for MM.

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Section: Discussionmentioning

confidence: 99%

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

et al. 2018

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“…Because IRF4 is a well-characterized myeloma survival factor, 28,29 we investigated whether IRF4 levels changed in cells that were overexpressing either the CD86FLm or CD86TLm constructs. We found that overexpression of CD86FLm led to a modest increase in IRF4 at both the mRNA and protein levels ( Figure 5C-D).…”

Section: Cytoplasmic Tail Of Cd86 Plays a Role In Cd28-cd86 Functionmentioning

confidence: 99%

CD86 regulates myeloma cell survival

et al. 2017

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Key Points• CD86 mediates myeloma survival via activity from its cytoplasmic tail and the CD28-CD86 interaction facilitates stromal independence.• Blocking the CD28-CD86 pathway is a promising therapeutic avenue for myeloma, as there are already approved agents that target this pathway.Although prognosis for patients with multiple myeloma has improved over the past decade, research toward discovery of new therapeutic avenues is important and could lead to a cure for this plasma cell malignancy. Here we show that blocking the CD28-CD86 pathway via silencing of either CD28 or CD86 leads to myeloma cell death. Inhibiting this pathway leads to downregulation of integrins and IRF4, a known myeloma survival factor. Our data also indicate that CD86, the canonical ligand in this pathway, has prosurvival activity that is dependent on its cytosolic domain. These findings indicate that targeting of this pathway is a promising therapeutic avenue for myeloma, because it leads to modulation of different processes important in cell viability.

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“…miR-125b could also protect the ethanol-induced apoptosis and embryotoxicity (35). Due to incomplete binding with the 3'-untranslated region of target mRNA, miR-125b may serve various roles in different diseases or processes (36,37). miRNA may regulate different genes and serve different functions.…”

Section: Discussionmentioning

confidence: 99%

miR-125b is associated with renal cell carcinoma cell migration, invasion and apoptosis

Jin

Zeng

et al. 2017

Oncology Letters

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Abstract. MicroRNA (miR)-125b has been identified as deregulated in a number of types of cancer. Previous studies have detected the expression of miR-125b in clear cell renal cell carcinoma (ccRCC) tissues by in situ hybridization and revealed that miR-125b was upregulated in ccRCC tissues, and was associated with recurrence and survival of patients with ccRCC. However, the function of miR-125b in RCC remains unclear. Thus, the expression of miR-125b was detected with quantitative polymerase chain reaction (qPCR) in 24 paired RCC and adjacent normal tissues. The result of qPCR showed that miR-125b was upregulated in RCC tissues. Furthermore, the function of miR-125b in RCC (786-O and ACHN) cells was detected by transfecting miR-125 mimic or inhibitor to upregulate or downregulate miR-125b expression. Cell proliferation assays (MTT and Cell Counting Kit-8), cell mobility assays (cell scratch and Transwell assay) and a cell apoptotic assay (flow cytometry assay) were performed to assess the function of miR-125b on RCC cells. Results from the assays demonstrated that overexpression of miR-125b could promote cell migration and invasion, and reduce the cell apoptotic rate. It was also revealed that downregulation of miR-125b could reduce cell migration and invasion, and induce cell apoptosis. However, the results of the cell proliferation assay revealed that miR-125b had no significant effect on cell proliferation. Not only could miR-125b predict recurrence and survival of ccRCC; the present study revealed that miR-125b could regulate RCC cell migration, invasion and apoptosis. Additional studies are required to determine the mechanism of miR-125b in RCC cells and define the target genes of miR-125b in RCC.

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Selective targeting of IRF4 by synthetic microRNA-125b-5p mimics induces anti-multiple myeloma activity in vitro and in vivo

Cited by 104 publications

References 52 publications

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

The diagnostic and prognostic value of plasma microRNA‑125b‑5p in patients with multiple myeloma

CD86 regulates myeloma cell survival

miR-125b is associated with renal cell carcinoma cell migration, invasion and apoptosis

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