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MiR-192 directly binds and regulates Dicer1 expression in neuroblastoma.

Feinberg-Gorenshtein G, Guedj A, Shichrur K, Jeison M, Luria D, Kodman Y, Ash S, Feinmesser M, Edry L, Shomron N, Weizman A, Yaniv I, Avigad S - PLoS ONE (2013)

Bottom Line: We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288.An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic.Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel ; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age. Reduced expression of Dicer1 has recently been shown to be in correlation with poor prognosis in NB patients. This study aimed to investigate the mechanisms that could lead to the down-regulation of Dicer1 in neuroblastoma. We used computational prediction to identify potential miRs down-regulating Dicer1 in neuroblastoma. One of the miRs that were predicted to target Dicer1 was miR-192. We measured the levels of miR-192 in 43 primary tumors using real time PCR. Following the silencing of miR-192, the levels of dicer1 cell viability, cell proliferation and migration capability were analyzed. Multivariate analysis identified miR-192 as an independent prognostic marker for relapse in neuroblastoma patients (p=0.04). We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288. An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic. Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.

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Kaplan Meier analysis by miR-192 expression.Kaplan Meier analysis for PFS by miR-192 expression: high and low miR-192 expression levels were determined as above or below the median expression level and were analyzed in (A) a whole cohort (n=43) and in (B) a cohort following exclusion of MYCNA (n= 36) .
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pone-0078713-g003: Kaplan Meier analysis by miR-192 expression.Kaplan Meier analysis for PFS by miR-192 expression: high and low miR-192 expression levels were determined as above or below the median expression level and were analyzed in (A) a whole cohort (n=43) and in (B) a cohort following exclusion of MYCNA (n= 36) .

Mentions: We analyzed the relative expression levels of the miRs in a cohort of 43 NB primary tumors. We did not detect a significant correlation between clinical parameters or outcome and expression levels of miR-103, miR-124, miR-612 or mir-125b-1. No significant association between miR-192 expression levels and clinical markers was identified. However, a significant correlation was detected with outcome at 10 years. Patients with low miR-192 expression levels had 76 % PFS versus 39% in patients expressing high miR-192 levels (p= 0.028; Figure 3A). Following the exclusion of MYCNA patients (n=36), the correlation became even stronger: patients with low miR-192 expression levels had 88 % PFS versus 40 % in patients with high miR-192 (p= 0.006; Figure 3B). Multivariate analysis including the variants stage, MYCN, HR group and miR-192, identified miR-192 as an independent prognostic marker for relapse (p= 0.04), in addition to the HR group (Table 1). A patient expressing high levels of miR-192 had a 2.9-fold increased risk to relapse.


MiR-192 directly binds and regulates Dicer1 expression in neuroblastoma.

Feinberg-Gorenshtein G, Guedj A, Shichrur K, Jeison M, Luria D, Kodman Y, Ash S, Feinmesser M, Edry L, Shomron N, Weizman A, Yaniv I, Avigad S - PLoS ONE (2013)

Kaplan Meier analysis by miR-192 expression.Kaplan Meier analysis for PFS by miR-192 expression: high and low miR-192 expression levels were determined as above or below the median expression level and were analyzed in (A) a whole cohort (n=43) and in (B) a cohort following exclusion of MYCNA (n= 36) .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3815303&req=5

pone-0078713-g003: Kaplan Meier analysis by miR-192 expression.Kaplan Meier analysis for PFS by miR-192 expression: high and low miR-192 expression levels were determined as above or below the median expression level and were analyzed in (A) a whole cohort (n=43) and in (B) a cohort following exclusion of MYCNA (n= 36) .
Mentions: We analyzed the relative expression levels of the miRs in a cohort of 43 NB primary tumors. We did not detect a significant correlation between clinical parameters or outcome and expression levels of miR-103, miR-124, miR-612 or mir-125b-1. No significant association between miR-192 expression levels and clinical markers was identified. However, a significant correlation was detected with outcome at 10 years. Patients with low miR-192 expression levels had 76 % PFS versus 39% in patients expressing high miR-192 levels (p= 0.028; Figure 3A). Following the exclusion of MYCNA patients (n=36), the correlation became even stronger: patients with low miR-192 expression levels had 88 % PFS versus 40 % in patients with high miR-192 (p= 0.006; Figure 3B). Multivariate analysis including the variants stage, MYCN, HR group and miR-192, identified miR-192 as an independent prognostic marker for relapse (p= 0.04), in addition to the HR group (Table 1). A patient expressing high levels of miR-192 had a 2.9-fold increased risk to relapse.

Bottom Line: We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288.An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic.Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.

View Article: PubMed Central - PubMed

Affiliation: Molecular Oncology, Felsenstein Medical Research Center, Petah Tikva, Israel ; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Neuroblastoma (NB) arises from the embryonic neural crest and is the most common extracranial solid tumor in children under 5 years of age. Reduced expression of Dicer1 has recently been shown to be in correlation with poor prognosis in NB patients. This study aimed to investigate the mechanisms that could lead to the down-regulation of Dicer1 in neuroblastoma. We used computational prediction to identify potential miRs down-regulating Dicer1 in neuroblastoma. One of the miRs that were predicted to target Dicer1 was miR-192. We measured the levels of miR-192 in 43 primary tumors using real time PCR. Following the silencing of miR-192, the levels of dicer1 cell viability, cell proliferation and migration capability were analyzed. Multivariate analysis identified miR-192 as an independent prognostic marker for relapse in neuroblastoma patients (p=0.04). We were able to show through a dual luciferase assay and side-directed mutational analysis that miR-192 directly binds the 3' UTR of Dicer1 on positions 1232-1238 and 2282-2288. An increase in cell viability, proliferation and migration rates were evident in NB cells transfected with miR-192-mimic. Yet, there was a significant decrease in proliferation when NB cells were transfected with an miR-192-inhibitor We suggest that miR-192 might be a key player in NB by regulating Dicer1 expression.

Show MeSH
Related in: MedlinePlus