can also block expression of transcription factors that positively regulate MT1-MMP expression. miR-145 down regulates HIF-2 by targeting its 3′-UTR, and by decreasing the level of this transcription factor, repressed expression of downstream genes cyclin D1, VEGF, and MT1-MMP, and via this means, tumor cell growth, invasion, and metastasis. miRNAs can also negatively regulate MT1-MMP expression by directly blocking MT1-MMP mRNA translation. In this light, decreased MT1-MMP expression by miR-9, miR-133a, and miR-24 is achieved by directly targeting putative binding sites in the 3′-UTR of MT1-MMP mRNA. The differences in tumor cell MT1-MMP expression response to KU55933 miR-335 may lie in differences in tissue specificity reflected in predominance of certain cellular regulatory pathways and the overall balance of genes targeted by miR-335. Utilizing bioinformatics data, Yan et al. determined 255 genes were predicted as targeted by miR-335 and many of these were in the same pathways such as p53, MAPK, TGF, Wnt, ERbB, mTOR, and focal adhesion. MT1-MMP was not indicated as a target, nor did we find a 7 / 12 MiR-335 Oncogenic Response Associated with MT1-MMP Fig 4. The effect of miR-335 on cell proliferation. Cell proliferation was measured using the CCK-8 assay. Increased levels of proliferation in miR-335 treated cells were found at 72 and 96 hrs for HT-1080, 96 hrs for BPH-1, and 72 hrs for U87GM cells. There was no change in rate of proliferation in HCT116, and a decrease in proliferation of MCF7 and MDA-MB-231 cells. doi:10.1371/journal.pone.0132026.g004 binding site in the 3′-UTR of MT1-MMP in the NCBI Database utilizing TargetScanHuman. Our data suggest that the differences in response to miR-335 by tumor cells may lie in part in the mechanism of regulation of MT1-MMP production. The HT-1080 and BPH-1 cells which responded to miR-335 with increased cell surface MT1-MMP localization, and U-87 cells, which did not respond to miR-335 but already had a strong presence of MT1-MMP on the cell surface, were stimulated to proliferate by miR-335. U87 cells, which had a higher endogenous level of miR-335 than HT-1080 and BPH-1 cells, 8 / 12 MiR-335 Oncogenic Response Associated with MT1-MMP have a significant amplification of the miR-335 locus and may have sufficient endogenous miR-335 so that an additional MT1-MMP response to miR-335 is not observed. Those cell lines with little or no cell surface MT1-MMP activity did not respond to miR-335 with proliferation. miR-335 appears to control growth by blocking cell PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/1974409 proliferation PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19741728 by targeting certain genes; e.g., RASA1 in rat epididymal development, SP1 and Bcl-w in non-small cell lung cancer, SOX4 and TNC in breast cancer, ROCK1, MAPK1, and LRG1 in neuroblastoma, and Rb1 in U2OS osteosarcoma cells. Thus, decreasing levels of miR-335 rescues cells from their negative regulatory mechanisms resulting in increased growth and invasive character of the tumor. On the other hand, miR-335 can target genes that suppress cell proliferation. Cell proliferation is increased in U87 cells via Wnt/PCP signaling by miR-335 decreasing DAAM expression and miR-335 targets RB1 in meningioma cells resulting in increased cell growth and inhibited cell cycle arrest at the GO/G1 transition. Up-regulation of miR335 in glioma cells reduces expression of PAX6, thus promoting cell proliferation and is accompanied by increased protein levels of MMP-2 and MMP-9. These data indicate miR-335 has a complex role in tumorigenesis and its reg

The loss at protein levels correlated with that at transcript levels

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