Glioblastoma multiforme (GBM) is an incurable form of brain cancer with a very poor prognosis. Because of its highly invasive nature, it is impossible to remove all tumor cells during surgical resection, making relapse inevitable. Further research into the regulatory mechanism underpinning GBM pathogenesis is therefore warranted, and over the past decade, there has been an increased focus on the functional role of microRNA (miRNA). This systematic review aims to present a comprehensive overview of all the available literature on the expression profiles and function of miRNA in GBM. Here, we have reviewed 163 papers and identified 253 upregulated, 95 downregulated, and 17 disputed miRNAs with respect to expression levels; 85 % of these miRNAs have not yet been functionally characterized. A focus in this study has been 26 interesting miRNAs involved in the mesenchymal mode of migration and invasion, demonstrating the importance of miRNAs in the context of the cellular niche. Both oncogenic and tumor-suppressive miRNAs were found to affect target genes involved in cell migration, cytoskeletal rearrangement, invasiveness, and angiogenesis. Clearly, the distinct functional properties of these miRNAs need further investigation and might hold a great potential in future molecular therapies targeting GBM.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-012-8349-7) contains supplementary material, which is available to authorized users.
The Arabidopsis gene FCA encodes an RNA binding protein that functions to promote the floral transition. The FCA transcript is alternatively processed to yield four transcripts, the most abundant of which is polyadenylated within intron 3. We have analyzed the role of the alternative processing on the floral transition. The introduction of FCA intronless transgenes resulted in increased FCA protein levels and accelerated flowering, but no role in flowering was found for products of the shorter transcripts. The consequences of the alternative processing on the FCA expression pattern were determined using a series of translational FCA- -glucuronidase fusions. The inclusion of FCA genomic sequence containing the alternatively processed intron 3 restricted the expression of the transgene predominantly to shoot and root apices and young flower buds. Expression of this fusion also was delayed developmentally. Therefore, the alternative processing of the FCA transcript limits, both spatially and temporally, the amount of functional FCA protein. Expression in roots prompted an analysis of root development, which indicated that FCA functions more generally than in the control of the floral transition. INTRODUCTIONThe transition to flowering in Arabidopsis is regulated by multiple environmental and developmental cues. Genetic pathways mediating the response to these cues have been defined. These pathways, composed of both floral promoters and repressors, redundantly activate sets of genes that are necessary to form a floral meristem (reviewed by Levy and Dean, 1998;Simpson et al., 1999;Colasanti and Sundaresan, 2000;Samach and Coupland, 2000). The major floral repressors FRIGIDA ( FRI ) and FLOWERING LOCUS C ( FLC ) have been characterized through the analysis of naturally occurring late-flowering accessions. The genes promoting the floral transition, components of the autonomous, photoperiod, vernalization, and gibberellin floral pathways, were identified chiefly through the analysis of lateflowering mutants.Three floral pathways determine whether a plant requires a long period of cold temperature for flowering (vernalization requirement) and how flowering is accelerated by cold temperature (vernalization response). FRI -mediated repression confers a dominant vernalization requirement by increasing RNA levels of the floral repressor FLC (Michaels and Amasino, 1999;Sheldon et al., 1999Sheldon et al., , 2000. Vernalization acts antagonistically to FRI by reducing FLC RNA levels (Michaels and Amasino, 1999;Sheldon et al., 1999Sheldon et al., , 2000. Recessive mutations in genes of the autonomous promotion pathway (e.g., in the FCA gene) cause an increase in FLC RNA levels and a late-flowering phenotype that can be rescued by vernalization. Therefore, the autonomous promotion pathway is considered to act in parallel with vernalization.To further understand the molecular mechanisms involved in these floral pathways, we have been analyzing FCA as one component of the autonomous floral pathway (Macknight et al., 1997). FCA enc...
The post-transcriptional regulator molecules, microRNAs, have emerged as important biomarkers and modulators of numerous pathophysiological processes including oncogenesis and cardiovascular diseases. Recently, a significant number of dysregulations in microRNAs have been reported in patients suffering from painful disorders such as complex regional pain syndrome, cystitis-induced chronic pain and irritable bowel disorder, in both affected tissues and the circulation. Moreover, microRNAs are known to be involved in pain processing based on several recent findings in animal models of inflammatory and neuropathic pain. The basis of this review was to cover and summarize available articles in English encompassing "microRNA and pain". In animal pain models widespread microRNA modulation is present and manifests on multiple levels i.e.: the dorsal root ganglia, the spinal dorsal horn and the brain. Numerous functional in vivo studies have found that dysregulated microRNAs are involved in the post-transcriptional modulation of genes implicated in pain generation and maintenance. Lastly, a few animal studies have delivered promising results as to the possibility of applying microRNAs as therapeutics to alleviate established pain and several clinical studies have highlighted the potential in applying microRNAs as biomarkers in painful conditions such as complex regional pain syndrome and fibromyalgia. This review briefly introduces the basics of microRNAs, their biogenesis and function, and mainly focuses on the recent advances made in understanding the role of microRNAs in relation to pain processing and painful conditions. It also provides an overview of widely diverse methodological approaches and results with a potential for future implications of microRNAs in the diagnosis and treatment of pain.
In the recent years, the possibility of utilizing extracellular vesicles for drug delivery purposes has been investigated in various models, suggesting that these vesicles may have such potential. In addition to the choice of donor cell type for vesicle production, a major obstacle still exists with respect of loading the extracellular vesicles efficiently with the drug of choice. One of the proposed solutions to this problem has been drug loading by electroporation, where small pores are created in the membrane of the extracellular vesicles, hereby allowing for free diffusion of the drug compound into the interior of the vesicle. We investigated the utility of adiposederived stem cells (ASCs) as an efficient exosome donor cell type with a particular focus on the treatment of glioblastoma multiforme (GBM). In addition, we evaluated electroporation-induced effects on the ASC exosomes with respect to their endogenous potential of stimulating GBM proliferation, and morphological changes to single and multiple ASC exosomes. We found that electroporation does not change the endogenous stimulatory capacity of ASC exosomes on GBM cell proliferation, but mediates adverse morphological changes including aggregation of the exosomes. In order to address this issue, we have successfully optimized the use of a trehalose-containing buffer system as a way of maintaining the structural integrity of the exosomes.
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