期刊
BIOLOGY DIRECT
卷 8, 期 -, 页码 -出版社
BMC
DOI: 10.1186/1745-6150-8-10
关键词
MiRNAs; Cluster; GBM; DLK1-DIO3; MEF2; Tumor Suppressor; Cancer
类别
资金
- Council of Scientific & Industrial Research (CSIR), India [NWP-0036]
- Department of Biotechnology (DBT), India [GAP-0094]
- ICMR-SRF
Background: MicroRNAs (miRNAs) are non-uniformly distributed in genomes and similar to 30% of the miRNAs in the human genome are clustered. In this study we have focused on the imprinted miRNA cluster miR-379/miR-656 on 14q32.31 (hereafter C14) to test their coordinated function. We have analyzed expression profile of >1000 human miRNAs in >1400 samples representing seven different human tissue types obtained from cancer patients along with matched and unmatched controls. Results: We found 68% of the miRNAs in this cluster to be significantly downregulated in glioblastoma multiforme (GBM), 61% downregulated in kidney renal clear cell carcinoma (KIRC), 46% in breast invasive carcinoma (BRCA) and 14% in ovarian serous cystadenocarcinoma (OV). On a genome-wide scale C14 miRNAs accounted for 12-30% of the total downregulated miRNAs in different cancers. Pathway enrichment for the predicted targets of C14 miRNA was significant for cancer pathways, especially Glioma (p<3.77x10(-6), FDR<0.005). The observed downregulation was confirmed in GBM patients by real-time PCR, where 79% of C14 miRNAs (34/43) showed downregulation. In GBM samples, hypermethylation at C14 locus (p<0.003) and downregulation of MEF2, a crucial transcription factor for the cluster was observed which likely contribute to the observed downregulation of the entire miRNA cluster. Conclusion: We provide compelling evidence that the entire C14 miRNA cluster is a tumor suppressor locus involved in multiple cancers, especially in GBM, and points toward a general mechanism of coordinated function for clustered miRNAs.
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