Matrix Metalloproteinases: Regulators of the Tumor Microenvironment

MicroRNAs (miRNAs) are a class of non-coding RNAs that play important roles in regulating gene expression. The majority of miRNAs are transcribed from DNA sequences into primary miRNAs and processed into precursor miRNAs, and finally mature miRNAs. In most cases, miRNAs interact with the 3' untranslated region (3' UTR) of target mRNAs to induce mRNA degradation and translational repression. However, interaction of miRNAs with other regions, including the 5' UTR, coding sequence, and gene promoters, have also been reported. Under certain conditions, miRNAs can also activate translation or regulate transcription. The interaction of miRNAs with their target genes is dynamic and dependent on many factors, such as subcellular location of miRNAs, the abundancy of miRNAs and target mRNAs, and the affinity of miRNA-mRNA interactions. miRNAs can be secreted into extracellular fluids and transported to target cells via vesicles, such as exosomes, or by binding to proteins, including Argonautes. Extracellular miRNAs function as chemical messengers to mediate cell-cell communication. In this review, we provide an update on canonical and non-canonical miRNA biogenesis pathways and various mechanisms underlying miRNA-mediated gene regulations. We also summarize the current knowledge of the dynamics of miRNA action and of the secretion, transfer, and uptake of extracellular miRNAs.

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Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation.

The journal of neuroscience : the official journal of the Society for Neuroscience.

MicroRNAs (miRNAs) are small RNAs that post-transcriptionally regulate the expression of thousands of genes in a broad range of organisms in both normal physiological contexts and in disease contexts. miRNA expression profiling is gaining popularity because miRNAs, as key regulators in gene expression networks, can influence many biological processes and also show promise as biomarkers for disease. Technological advances have spawned a multitude of platforms for miRNA profiling, and an understanding of the strengths and pitfalls of different approaches can aid in their effective use. Here, we review the major considerations for carrying out and interpreting results of miRNA-profiling studies.

MicroRNA profiling: approaches and considerations.

Since the discovery of microRNAs (miRNAs), the study of these small noncoding RNAs has steadily increased and more than 10,000 papers have already been published. The great interest in miRNAs reflects their central role in gene-expression regulation and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, immune-related and other diseases. Another avenue of current research is the study of circulating miRNAs in serum, plasma, and other body fluids--miRNAs may act not only within cells, but also at other sites within the body. The presence of miRNAs in body fluids may represent a gold mine of noninvasive biomarkers in cancer. Since deregulated miRNA expression is an early event in tumorigenesis, measuring circulating miRNA levels may also be useful for early cancer detection, which can contribute greatly to the success of treatment. In this Review, we discuss the role of fluid-expressed miRNAs as reliable cancer biomarkers and treatment-response predictors as well as potential new patient selection criteria for clinical trials. In addition, we explore the concept that miRNAs could function as hormones.

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MicroRNAs in body fluids—the mix of hormones and biomarkers

BACKGROUND: MicroRNAs (miRNAs) are small, noncoding RNAs that play an important role in regulating various biological processes through their interaction with cellular messenger RNAs. Extracellular miRNAs in serum, plasma, saliva, and urine have recently been shown to be associated with various pathological conditions including cancer. METHODS: With the goal of assessing the distribution of miRNAs and demonstrating the potential use of miRNAs as biomarkers, we examined the presence of miRNAs in 12 human body fluids and urine samples from women in different stages of pregnancy or patients with different urothelial cancers. Using quantitativePCR,weconductedaglobalsurveyofthemiRNA distribution in these fluids. RESULTS: miRNAs were present in all fluids tested and showed distinct compositions in different fluid types. Several of the highly abundant miRNAs in these fluids werecommonamongmultiplefluidtypes,andsomeof the miRNAs were enriched in specific fluids. We also observeddistinctmiRNApatternsintheurinesamples obtained from individuals with different physiopathological conditions. CONCLUSIONS: MicroRNAs are ubiquitous in all the body fluid types tested. Fluid type–specific miRNAs may have functional roles associated with the surrounding tissues. In addition, the changes in miRNA spectra observed in the urine samples from patients with different urothelial conditions demonstrates the potential for using concentrations of specific miRNAs in body fluids as biomarkers for detecting and monitoring various physiopathological conditions. © 2010 American Association for Clinical Chemistry

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The MicroRNA Spectrum in 12 Body Fluids

Objectives: The aim of this study was to investigate the association of the complex haplotype system of the adenosine triphosphate-binding cassette B1 (ABCB1) gene with the epilepsy treatment response. Methods and results: Ten polymorphisms were genotyped in 108 drug-resistant epileptic patients, 223 seizure-free patients and 287 normal controls. Highly significant linkage disequilibrium was shown among exon 12 C1236T, exon 21 G2677T and exon 26 C3435T. Haplotypic analysis demonstrated that patients with the CGC, TGC, and TTT haplotypes were more likely to be drug resistant. Further analysis of haplotype combinations demonstrated that drug-resistant patients tended to have the CGC/CGC, CGC/TGC, CGC/TTT, and TGC/TTT haplotype combinations over the seizure-free patients and controls (all p-values < 0.0001). In contrast, patients with the TTC/TTC, TTC/CGT, TTC/TGT, CGT/CGT and TGT/CGT haplotype combinations were more likely to be seizure-free (all p-values < 0.0001 except CGT/CGT [p = 0.0063]). Conclusion: O...

Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response.

Purpose of reviewThis review summarizes the recent clinical and genetic developments in neurofibromatosis type 1 (NF1) and provides an insight into the possible underlying pathomechanisms.Recent findingsNF1, or von Recklinghausen disease, is one of the most common hereditary neurocutaneous disorders

Recent developments in neurofibromatosis type 1.

Leptin, the product of the obese gene, plays an important role in the regulation of body weight by coordinating metabolism, feeding behavior, energy balance, and neuroendocrine responses. However, regulation of leptin gene expression in the central nervous system is different from that in the adipocytes. In addition, leptin has been found in many tumor cell lines and has been shown to have mitogenic and angiogenic activity in a number of cell types. Glioma is the most common primary adult brain tumor with poor prognosis because of the spreading of tumor cell to the other regions of brain easily. Here we found that malignant C6 glioma cells expressed more leptin and leptin receptors than nonmalignant astrocytes. Furthermore, it was found that exogenous application of leptin enhanced the migration and invasion of C6 glioma cells. In addition, we found that the expression of matrix metalloproteinase-13 (MMP-13) but not of MMP-2 and MMP-9 was increased in response to leptin stimulation. The leptin-induced increase of cell migration and invasion was antagonized by MMP-13 neutralizing antibody or silencing MMP-13. The up-regulation of MMP-13 induced by leptin was mainly through p38 MAP kinase and NF-kappaB pathway. In addition, migration-prone sublines demonstrate that cells with increasing migration ability had more expression of MMP-13 and leptin. Taken together, these results indicate that leptin enhanced migration and invasion of C6 glioma cells through the increase of MMP-13 production.

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Leptin induces migration and invasion of glioma cells through MMP-13 production

Dental caries arises from an imbalance of metabolic activities in dental biofilms developed primarily by Streptococcus mutans. This study was conducted to isolate potential oral probiotics with antagonistic activities against S. mutans biofilm formation from Lactobacillus salivarius, frequently found in human saliva. We analysed 64 L. salivarius strains and found that two, K35 and K43, significantly inhibited S. mutans biofilm formation with inhibitory activities more pronounced than those of Lactobacillus rhamnosus GG (LGG), a prototypical probiotic that shows anti-caries activity. Scanning electron microscopy showed that co-culture of S. mutans with K35 or K43 resulted in significantly reduced amounts of attached bacteria and network-like structures, typically comprising exopolysaccharides. Spot assay for S. mutans indicated that K35 and K43 strains possessed a stronger bactericidal activity against S. mutans than LGG. Moreover, quantitative real-time polymerase chain reaction showed that the expression of genes encoding glucosyltransferases, gtfB, gtfC, and gtfD was reduced when S. mutans were co-cultured with K35 or K43. However, LGG activated the expression of gtfB and gtfC, but did not influence the expression of gtfD in the co-culture. A transwell-based biofilm assay indicated that these lactobacilli inhibited S. mutans biofilm formation in a contact-independent manner. In conclusion, we identified two L. salivarius strains with inhibitory activities on the growth and expression of S. mutans virulence genes to reduce its biofilm formation. This is not a general characteristic of the species, so presents a potential strategy for in vivo alteration of plaque biofilm and caries.

Ming-Jen Lee

Papers

The MicroRNA Spectrum in 12 Body Fluids

Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response.

Recent developments in neurofibromatosis type 1.

Leptin induces migration and invasion of glioma cells through MMP-13 production

Inhibitory effect of Lactobacillus salivarius on Streptococcus mutans biofilm formation.