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Low expression of miR-196b enhances the expression of BCR-ABL1 and HOXA9 oncogenes in chronic myeloid leukemogenesis.

Liu Y, Zheng W, Song Y, Ma W, Yin H - PLoS ONE (2013)

Bottom Line: The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05), which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands.A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia.MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetic Engineering, Southern Medical University, Guangzhou, China.

ABSTRACT
MicroRNAs (miRNAs) can function as tumor suppressors or oncogene promoters during tumor development. In this study, low levels of expression of miR-196b were detected in patients with chronic myeloid leukemia. Bisulfite genomic sequencing PCR and methylation-specific PCR were used to examine the methylation status of the CpG islands in the miR-196b promoter in K562 cells, patients with leukemia and healthy individuals. The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05), which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands. The dual-luciferase reporter assay system demonstrated that BCR-ABL1 and HOXA9 are the target genes of miR-196b, which was consistent with predictions from bioinformatics software analyses. Further examination of cell function indicated that miR-196b acts to reduce BCR-ABL1 and HOXA9 protein levels, decrease cell proliferation rate and retard the cell cycle. A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia. MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

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Target gene prediction, plasmid constructs and lentivirus infection.(A) Target genes of miR-196b, predicted by TargetScan. (B) Target genes of miR-196b, predicted by miRanda. (C) Target genes of miR-196b predicted by miRNA Viewer. (D1): BCR-ABL1-3′-UTR, (D2): HOXA9-3′-UTR. (E1): BCR-ABL1-3′-UTR-mut-1, (E2): BCR-ABL1-3′-UTR-mut-2, (E3): BCR-ABL1-3′-UTR-mutant. (F1): HOXA9-3′-UTR-mut-1, (F2): HOXA9-3′-UTR-mut-2, (F3): HOXA9-3′-UTR-mut-3, (F4): HOXA9-3′-UTR-mutant. (G): pre-miR-196b. (H): K562 cells infected by 196b virus (10×). (I): K562 cells infected by pLV virus (10×).
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pone-0068442-g002: Target gene prediction, plasmid constructs and lentivirus infection.(A) Target genes of miR-196b, predicted by TargetScan. (B) Target genes of miR-196b, predicted by miRanda. (C) Target genes of miR-196b predicted by miRNA Viewer. (D1): BCR-ABL1-3′-UTR, (D2): HOXA9-3′-UTR. (E1): BCR-ABL1-3′-UTR-mut-1, (E2): BCR-ABL1-3′-UTR-mut-2, (E3): BCR-ABL1-3′-UTR-mutant. (F1): HOXA9-3′-UTR-mut-1, (F2): HOXA9-3′-UTR-mut-2, (F3): HOXA9-3′-UTR-mut-3, (F4): HOXA9-3′-UTR-mutant. (G): pre-miR-196b. (H): K562 cells infected by 196b virus (10×). (I): K562 cells infected by pLV virus (10×).

Mentions: The TargetScan software predicted that BCR-ABL1 and HOXA9, which are closely associated with CML, are target genes of miR-196b (Figure 2A). Both miRanda (Figure 2B) and miRNA Viewer (Figure 2C) software predicted that the target genes of miR-196b included HOXA9. In contrast, the PicTar software failed to identify any target genes of miR-196b. Overall, these results indicated that BCR-ABL1 and HOXA9 are likely to be target genes of miR-196b.


Low expression of miR-196b enhances the expression of BCR-ABL1 and HOXA9 oncogenes in chronic myeloid leukemogenesis.

Liu Y, Zheng W, Song Y, Ma W, Yin H - PLoS ONE (2013)

Target gene prediction, plasmid constructs and lentivirus infection.(A) Target genes of miR-196b, predicted by TargetScan. (B) Target genes of miR-196b, predicted by miRanda. (C) Target genes of miR-196b predicted by miRNA Viewer. (D1): BCR-ABL1-3′-UTR, (D2): HOXA9-3′-UTR. (E1): BCR-ABL1-3′-UTR-mut-1, (E2): BCR-ABL1-3′-UTR-mut-2, (E3): BCR-ABL1-3′-UTR-mutant. (F1): HOXA9-3′-UTR-mut-1, (F2): HOXA9-3′-UTR-mut-2, (F3): HOXA9-3′-UTR-mut-3, (F4): HOXA9-3′-UTR-mutant. (G): pre-miR-196b. (H): K562 cells infected by 196b virus (10×). (I): K562 cells infected by pLV virus (10×).
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3716876&req=5

pone-0068442-g002: Target gene prediction, plasmid constructs and lentivirus infection.(A) Target genes of miR-196b, predicted by TargetScan. (B) Target genes of miR-196b, predicted by miRanda. (C) Target genes of miR-196b predicted by miRNA Viewer. (D1): BCR-ABL1-3′-UTR, (D2): HOXA9-3′-UTR. (E1): BCR-ABL1-3′-UTR-mut-1, (E2): BCR-ABL1-3′-UTR-mut-2, (E3): BCR-ABL1-3′-UTR-mutant. (F1): HOXA9-3′-UTR-mut-1, (F2): HOXA9-3′-UTR-mut-2, (F3): HOXA9-3′-UTR-mut-3, (F4): HOXA9-3′-UTR-mutant. (G): pre-miR-196b. (H): K562 cells infected by 196b virus (10×). (I): K562 cells infected by pLV virus (10×).
Mentions: The TargetScan software predicted that BCR-ABL1 and HOXA9, which are closely associated with CML, are target genes of miR-196b (Figure 2A). Both miRanda (Figure 2B) and miRNA Viewer (Figure 2C) software predicted that the target genes of miR-196b included HOXA9. In contrast, the PicTar software failed to identify any target genes of miR-196b. Overall, these results indicated that BCR-ABL1 and HOXA9 are likely to be target genes of miR-196b.

Bottom Line: The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05), which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands.A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia.MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetic Engineering, Southern Medical University, Guangzhou, China.

ABSTRACT
MicroRNAs (miRNAs) can function as tumor suppressors or oncogene promoters during tumor development. In this study, low levels of expression of miR-196b were detected in patients with chronic myeloid leukemia. Bisulfite genomic sequencing PCR and methylation-specific PCR were used to examine the methylation status of the CpG islands in the miR-196b promoter in K562 cells, patients with leukemia and healthy individuals. The CpG islands showed more methylation in patients with chronic myeloid leukemia compared with healthy individuals (P<0.05), which indicated that low expression of miR-196b may be associated with an increase in the methylation of CpG islands. The dual-luciferase reporter assay system demonstrated that BCR-ABL1 and HOXA9 are the target genes of miR-196b, which was consistent with predictions from bioinformatics software analyses. Further examination of cell function indicated that miR-196b acts to reduce BCR-ABL1 and HOXA9 protein levels, decrease cell proliferation rate and retard the cell cycle. A low level of expression of miR-196b can cause up-regulation of BCR-ABL1 and HOXA9 expression, which leads to the development of chronic myeloid leukemia. MiR-196b may represent an effective target for chronic myeloid leukemia therapy.

Show MeSH
Related in: MedlinePlus