407021

MIR29A

MIRN29|MIRN29A|hsa-mir-29|hsa-mir-29a|miRNA29A;microRNA 29a;MIR29A;microRNA 29a

microRNA 29

7q32.3

ncRNA

microRNAs (miRNAs) are small noncoding RNAs which play essential roles in many important biological processes. Therefore, their dysfunction is associated with a variety of human diseases, including cancer. Increasing evidence shows that miRNAs can act as oncogenes or tumor suppressors, and although there is great interest in research into these cancer-associated miRNAs, little is known about them. In this study, we performed a comprehensive analysis of putative human miRNA oncogenes and tumor suppressors. We found that miRNA oncogenes and tumor suppressors clearly show different patterns in function, evolutionary rate, expression, chromosome distribution, molecule size, free energy, transcription factors, and targets. For example, miRNA oncogenes are located mainly in the amplified regions in human cancers, whereas miRNA tumor suppressors are located mainly in the deleted regions. miRNA oncogenes tend to cleave target mRNAs more frequently than miRNA tumor suppressors. These results indicate that these two types of cancer-associated miRNAs play different roles in cancer formation and development. Moreover, the patterns identified here can discriminate novel miRNA oncogenes and tumor suppressors with a high degree of accuracy. This study represents the first large-scale bioinformatic analysis of human miRNA oncogenes and tumor suppressors. Our findings provide help for not only understanding of miRNAs in cancer but also for the specific identification of novel miRNAs as miRNA oncogenes and tumor suppressors. In addition, the data presented in this study will be valuable for the study of both miRNAs and cancer.

In sarcoma, the activity of NF-kappaB (nuclear factor kappaB) reduces the abundance of the microRNA (miRNA) miR-29. The tumor suppressor A20 [also known as TNFAIP3 (tumor necrosis factor-alpha-induced protein 3)] inhibits an upstream activator of NF-kappaB and is often mutated in lymphomas. In a panel of human sarcoma cell lines, we found that the activation of NF-kappaB was increased and, although the abundance of A20 protein and mRNA was decreased, the gene encoding A20 was rarely mutated. The 3 untranslated region (UTR) of A20 mRNA has conserved binding sites for both of the miRNAs miR-29 and miR-125. Whereas the expression of miR-125 was increased in human sarcoma tissue, that of miR-29 was decreased in most samples. Overexpression of miR-125 decreased the abundance of A20 mRNA, whereas reconstituting miR-29 in sarcoma cell lines increased the abundance of A20 mRNA and protein. By interacting directly with the RNA binding protein HuR (human antigen R; also known as ELAVL1), miR-29 prevented HuR from binding to the A20 3UTR and recruiting the RNA degradation complex RISC (RNA-induced silencing complex), suggesting that miR-29 can act as a decoy for HuR, thus protecting A20 transcripts. Decreased miR-29 and A20 abundance in sarcomas correlated with increased activity of NF-kappaB and decreased expression of genes associated with differentiation. Together, the findings reveal a unique role of miR-29 and suggest that its absence may contribute to sarcoma tumorigenesis.

The tumor necrosis factor receptor (TNFR)-associated factor 4 (TRAF4) is a member of TRAF family proteins that act as major signal transducers of the TNF receptor and the interleukin-1 receptor/Toll-like receptor (IL-1R/TLR) superfamily. TRAF4 has been reported to be overexpressed in various human cancers. However, the exact mechanisms that regulate the expression of TRAF4 still remain elusive. The objective of the present study was to investigate the regulatory mechanism of TRAF4 expression in prostate cancer. We initially identified microRNA-29a (miR29a) as a possible candidate to bind TRAF4 3 untranslated region (3UTR) by the algorithm, TargetScan. The expression of TRAF4 mRNA and protein was inversely associated with miR-29a expression in prostate cancer cell lines (LNCaP, DU145 and PC3). TRAF4 expression was reduced by the introduction of mimic miR-29a in LNCaP cells. Luciferase activity from the construct harboring wild-type TRAF4 3UTR was reduced by the mimic miR-29a and this reduction was diminished by introducing mutations at the predicted miR-29a binding site. On the other hand, TRAF4 was upregulated when transfected with the inhibitor of miR-29a in DU145 and PC3 cells. TRAF4 was significantly upregulated in patients with metastatic prostate cancer compared to those with localized prostate cancer. Furthermore, there was a significant inverse correlation between TRAF4 and miR-29a expression in tumor tissues from radical prostatectomy. Considered together, our results suggest that the tumor suppressor microRNA, miR-29a, is one of the regulators of TRAF4 expression in metastatic prostate cancer.