MicroRNAs (miRNAs) are small non-coding RNAs of ∼ 22 nucleotides that are involved in negative regulation of mRNA at the post-transcriptional level. Previously, we developed miRTarBase which provides information about experimentally validated miRNA-target interactions (MTIs). Here, we describe an updated database containing 422 517 curated MTIs from 4076 miRNAs and 23 054 target genes collected from over 8500 articles. The number of MTIs curated by strong evidence has increased ∼1.4-fold since the last update in 2016. In this updated version, target sites validated by reporter assay that are available in the literature can be downloaded. The target site sequence can extract new features for analysis via a machine learning approach which can help to evaluate the performance of miRNA-target prediction tools. Furthermore, different ways of browsing enhance user browsing specific MTIs. With these improvements, miRTarBase serves as more comprehensively annotated, experimentally validated miRNA-target interactions databases in the field of miRNA related research. miRTarBase is available at http://miRTarBase.mbc.nctu.edu.tw/.
Background Hypertrophic scars (HSs) are formed via an aberrant response to the wound healing process. HSs can be cosmetic or can result in functional problems. Prolonged proliferation and remodeling phases disrupt wound healing, leading to excessive collagen production and HS formation. However, there are currently no satisfactory drugs to prevent HS formation. Mesenchymal stem cell (MSC) conditioned medium (CM) has therapeutic effects on wound healing and preventing HS formation. Bone marrow concentrate (BMC) contains various growth factors and cytokines that are crucial for regeneration and has been applied in the clinical setting. In this study, we evaluated the effects of BMC-induced MSC CM on HS formation in a rabbit ear model. Methods We established a rabbit ear wound model by generating full-thickness wounds in the ears of rabbits ( n = 12) and treated wounds with MSC CM, BMC CM, or BMC-induced MSC CM. Dermal fibroblasts from human hypertrophic scar were stimulated with transforming growth factor beta 1 (TGF-β1) for 24 h and cultured in each culture medium for 72 h. We measured the hypertrophic scar (HS) formation during the skin regeneration by measuring the expression of several remodeling molecules and the effect of these conditioned media on active human HS fibroblasts. Results Our results showed that BMC-induced MSC CM had greater antifibrotic effects than MSC CM and BMC CM significantly attenuated HS formation in rabbits. BMC-induced MSC CM accelerated wound re-epithelization by increasing cell proliferation. Additionally, BMC-induced MSC CM also inhibited fibrosis by decreasing profibrotic gene and protein expression, promoting extracellular matrix turnover, inhibiting fibroblast contraction, and reversing myofibroblast activation. Conclusions BMC-induced MSC CM modulated the proliferation and remodeling phases of wound healing, representing a potential wound healing agent and approach for preventing HS formation. Electronic supplementary material The online version of this article (10.1186/s13287-019-1383-x) contains supplementary material, which is available to authorized users.
Globally, breast cancer is the most frequently diagnosed cancer in women, and it remains a substantial clinical challenge due to cancer relapse. The presence of a subpopulation of dormant breast cancer cells that survived chemotherapy and metastasized to distant organs may contribute to relapse. Tumor microenvironment (TME) plays a significant role as a niche in inducing cancer cells into dormancy as well as involves in the reversible epithelial-to-mesenchymal transition (EMT) into aggressive phenotype responsible for cancer-related mortality in patients. Mesenchymal stem cells (MSCs) are known to migrate to TME and interact with cancer cells via secretion of exosome- containing biomolecules, microRNA. Understanding of interaction between MSCs and cancer cells via exosomal miRNAs is important in determining the therapeutic role of MSC in treating breast cancer cells and relapse. In this study, exosomes were harvested from a medium of indirect co-culture of MCF7-luminal and MDA-MB-231-basal breast cancer cells (BCCs) subtypes with adipose MSCs. The interaction resulted in different exosomal miRNAs profiles that modulate essential signaling pathways and cell cycle arrest into dormancy via inhibition of metastasis and epithelial-to-mesenchymal transition (EMT). Overall, breast cancer cells displayed a change towards a more dormant-epithelial phenotype associated with lower rates of metastasis and higher chemoresistance. The study highlights the crucial roles of adipose MSCs in inducing dormancy and identifying miRNAs-dormancy related markers that could be used to identify the metastatic pattern, predict relapses in cancer patients and to be potential candidate targets for new targeted therapy.
Epithelial-to-mesenchymal transition (EMT) is a highly orchestrated process motivated by the nature of physical and chemical compositions of the tumor microenvironment (TME). The role of the physical framework of the TME in guiding cells toward EMT is poorly understood. To investigate this, breast cancer MDA-MB-231 and MCF-7 cells were cultured on nanochips comprising tantalum oxide nanodots ranging in diameter from 10 to 200 nm, fabricated through electrochemical approach and collectively referred to as artificial microenvironments. The 100 and 200 nm nanochips induced the cells to adopt an elongated or spindle-shaped morphology. The key EMT genes, E-cadherin, N-cadherin, and vimentin, displayed the spatial control exhibited by the artificial microenvironments. The E-cadherin gene expression was attenuated, whereas those of N-cadherin and vimentin were amplified by 100 and 200 nm nanochips, indicating the induction of EMT. Transcription factors, snail and twist, were identified for modulating the EMT genes in the cells on these artificial microenvironments. Localization of EMT proteins observed through immunostaining indicated the loss of cell-cell junctions on 100 and 200 nm nanochips, confirming the EMT induction. Thus, by utilizing an in vitro approach, we demonstrate how the physical framework of the TME may possibly trigger or assist in inducing EMT in vivo. Applications in the fields of drug discovery, biomedical engineering, and cancer research are expected.
Metastatic progression is mediated by complex interactions between deregulated extracellular matrix (ECM) and cancer cells and remains a major challenge in cancer management. To investigate the role of ECM dynamics in promoting metastasis development, we developed an artificial microenvironment (AME) platform comprised of nanodot arrays of increasing diameter. Cells cultured on the platform showed increasing signs of mesenchymallike cell transition as AME diameter increased, suggesting accurate simulation of ECM-mediated gene regulation. Gene expression was analyzed to determine genes significant to transition, which were then used to select appropriate small molecule drugs for time course treatments. Our results suggest that the platform can identify critical target genes as well as possible drug candidates. Overall, the AME platform allows for the study of intricate ECM-induced gene expression trends across metastasis development that would otherwise be difficult to visualize in vivo and may open new avenues toward successful personalized cancer management.
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