MicroRNAs as Regulators of Neural Stem Cell-Related Pathways in Glioblastoma Multiforme

MicroRNAs are endogenous non-coding small RNAs that have been described as highly conserved regulators of gene expression. They are involved in cancer and in the regulation of neural development and stem cell function. Recent studies suggest that a small subpopulation of cancer stem cells (CSCs) has the capacity to repopulate solid tumours such as glioblastoma (GBM), drive malignant progression and mediate radio- and chemoresistance. GBM-derived CSCs share the fundamental stem cell properties of self-renewal and multipotency with neural stem cells (NSCs) and may be regulated by miRNAs. In this review, we will summarize the current knowledge regarding the role of miRNAs in GBM development with a focus on the regulation of GBM-CSCs. We propose a list of miRNAs that could serve as molecular classifiers for GBMs and/or as promising therapeutic targets for such brain tumours.     

Functional Profiling of Precursor MicroRNAs Identifies MicroRNAs Essential for Glioma Proliferation

Cancer initiation and progression involve microRNAs that can function like tumor suppressors and oncogenes. The functional significance of most miRNAs is currently unknown. To determine systematically which microRNAs are essential for glioma growth, we screened a precursor microRNA library in three human glioblastoma and one astroglial cell line model systems. The most prominent and consistent cell proliferation–reducing hits were validated in secondary screening with an additional apoptosis endpoint. The functional screening data were integrated in the miRNA expression data to find underexpressed true functional tumor suppressor miRNAs. In addition, we used miRNA-target gene predictions and combined siRNA functional screening data to find the most probable miRNA-target gene pairs with a similar functional effect on proliferation. Nine novel functional miRNAs (hsa-miR-129, -136, -145, -155, -181b, -342-5p, -342-3p, -376a/b) in GBM cell lines were validated for their importance in glioma cell growth, and similar effects for six target genes (ROCK1, RHOA, MET, CSF1R, EIF2AK1, FGF7) of these miRNAs were shown functionally. The clinical significance of the functional hits was validated in miRNA expression data from the TCGA glioblastoma multiforme (GBM) tumor cohort. Five tumor suppressor miRNAs (hsa-miR-136, -145, -342, -129, -376a) showed significant underexpression in clinical GBM tumor samples from the TCGA GBM cohort further supporting the role of these miRNAs in vivo. Most importantly, higher hsa-miR-145 expression in GBM tumors yielded significantly better survival (p<0.005) in a subset of patients thus validating it as a genuine tumor suppressor miRNA. This systematic functional profiling provides important new knowledge about functionally relevant miRNAs in GBM biology and may offer new targets for treating glioma.     

A Systematic Review of MicroRNA in Glioblastoma Multiforme: Micro-modulators in the Mesenchymal Mode of Migration and Invasion

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.     

microRNAs in the regulation of adipogenesis and obesity

Worldwide obesity is a growing health problem, associated with increased risk of chronic disease. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation, insulin action and fat metabolism. Recent studies show miRNAs are dysregulated in obese adipose tissue. During adipogenesis miRNAs can accelerate or inhibit adipocyte differentiation and hence regulate fat cell development. In addition miRNAs may regulate adipogenic lineage commitment in multipotent stem cells and hence govern fat cell numbers. Recent findings suggest miR-519d may be associated with human obesity, but larger case-control studies are needed. Few miRNA targets have been experimentally validated in adipocytes but interestingly both miR-27 and miR-519d target PPAR family members, which are well established regulators of fat cell development. In this review recent advances in our understanding of the role of miRNAs in fat cell development and obesity are discussed. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.     

Downregulation of miR-31, miR-155, and miR-564 in chronic myeloid leukemia cells

Background/Aims

MicroRNAs (miRNAs) are short non-coding regulatory RNAs that control gene expression and play an important role in cancer development and progression. However, little is known about the role of miRNAs in chronic myeloid leukemia (CML). Our objective is to decipher a miRNA expression signature associated with CML and to determine potential target genes and signaling pathways affected by these signature miRNAs.

Results

Using miRNA microarrays and miRNA real-time PCR we characterized the miRNAs expression profile of CML cell lines and patients in reference to non-CML cell lines and healthy blood. Of all miRNAs tested, miR-31, miR-155, and miR-564 were down-regulated in CML cells. Down-regulation of these miRNAs was dependent on BCR-ABL activity. We next analyzed predicted targets and affected pathways of the deregulated miRNAs. As expected, in K562 cells, the expression of several of these targets was inverted to that of the miRNA putatively regulating them. Reassuringly, the analysis identified CML as the main disease associated with these miRNAs. MAPK, ErbB, mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF) were the main molecular pathways related with these expression patterns. Utilizing Venn diagrams we found appreciable overlap between the CML-related miRNAs and the signaling pathways-related miRNAs.

Conclusions

The miRNAs identified in this study might offer a pivotal role in CML. Nevertheless, while these data point to a central disease, the precise molecular pathway/s targeted by these miRNAs is variable implying a high level of complexity of miRNA target selection and regulation. These deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanism underlying the development of CML, and propose possible new avenues for therapeutic treatment.     

Big Effects of Small RNAs: A Review of MicroRNAs in Anxiety

Epigenetic and regulatory elements provide an additional layer of complexity to the heterogeneity of anxiety disorders. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that have recently drawn interest as epigenetic modulators of gene expression in psychiatric disorders. miRNAs elicit their effects by binding to target messenger RNAs (mRNAs) and hindering translation or accelerating degradation. Considering their role in neuronal differentiation and synaptic plasticity, miRNAs have opened up new investigative avenues in the aetiology and treatment of anxiety disorders. In this review, we provide a thorough analysis of miRNAs, their targets and their functions in the central nervous system (CNS), focusing on their role in anxiety disorders. The involvement of miRNAs in CNS functions (such as neurogenesis, neurite outgrowth, synaptogenesis and synaptic and neural plasticity) and their intricate regulatory role under stressful conditions strongly support their importance in the aetiology of anxiety disorders. Furthermore, miRNAs could provide new avenues for the development of therapeutic targets in anxiety disorders.     

胶质母细胞瘤外泌体的作用机制研究进展

胶质母细胞瘤(glioblastoma,GBM)因组织学异质性、侵袭能力强、术后复发快等问题,致使患者经手术治疗、化疗和放疗后的预后差,总体生存期短。GBM细胞来源外泌体(GBM cell-derived exosome,GBM-exo)能够通过其携带的细胞因子、miRNA、DNA和蛋白质等调节GBM细胞的增殖和迁移,通过血管生成蛋白和非编码RNA促进肿瘤血管生成,通过调节因子、蛋白质和药物靶向免疫检查点等介导肿瘤免疫逃逸,以及通过非编码RNA对抗GBM细胞的耐药性,有望成为个性化治疗GBM的重要靶标,且可以作为GBM的诊断和预后标志物。本文阐述了GBM-exo的制备方法和生物学特征,及其在GBM细胞增殖、血管生成、免疫逃逸和耐药性方面的作用和分子机制,为研发诊治GBM的新策略提供参考。     

Regulatory MicroRNA Networks:Complex Patterns of Target Pathways for Disease-related and Housekeeping MicroRNAs

Blood-based micro RNA(mi RNA) signatures as biomarkers have been reported for various pathologies, including cancer, neurological disorders, cardiovascular diseases, and also infections. The regulatory mechanism behind respective mi RNA patterns is only partially understood. Moreover, ‘‘preserved' mi RNAs, i.e., mi RNAs that are not dysregulated in any disease,and their biological impact have been explored to a very limited extent. We set out to systematically determine their role in regulatory networks by defining groups of highly-dysregulated mi RNAs that contribute to a disease signature as opposed to preserved housekeeping mi RNAs. We further determined preferential targets and pathways of both dysregulated and preserved mi RNAs by computing multi-layer networks, which were compared between housekeeping and dysregulated mi RNAs. Of 848 mi RNAs examined across 1049 blood samples, 8 potential housekeepers showed very limited expression variations, while 20 mi RNAs showed highly-dysregulated expression throughout the investigated blood samples. Our approach provides important insights into mi RNAs and their role in regulatory networks. The methodology can be applied to systematically investigate the differences in target genes and pathways of arbitrary mi RNA sets.     

miR-373 Inhibits Glioma Cell U251 Migration and Invasion by Down-Regulating CD44 and TGFBR2

Glioblastoma multiforme (GBM) is the most malignant glioma, unveiling the underlying mechanisms of its aggressiveness could promote the discovery of potential targets for effective treatment. MicroRNAs (miRNAs) are important participants in both development and disease, its involvement in cancers has long been recognized. In this study, we investigated the role of miRNA-373 (miR-373) in GBM cell line U251, demonstrated that although miR-373 does not affect cell growth of U251, it inhibits migration and invasion of U251. Forced expression of miR-373 down-regulates the expressions CD44 and TGFBR2, while knockdown of CD44 and TGFBR2 presents the similar phenotype as miR-373 overexpression, suggesting that CD44 and TGFBR2 are functional targets of miR-373, down-regulation of CD44 and TGFBR2 by miR-373 are partly responsible for the migration, and invasion suppressive role of miR-373 in U251.