Interaction between Wnt/β-catenin pathway and microRNAs regulates epithelial-mesenchymal transition in gastric cancer (Review)
Int J Oncol. 2016 Apr 8. doi: 10.3892/ijo.2016.3480. [Epub ahead of print]
Wu C1, Zhuang Y1, Jiang S2, Liu S1, Zhou J1, Wu J1, Teng Y1, Xia B1, Wang R1, Zou X1. Author information Abstract Gastric cancer (GC) is the third primary cause of cancer-related mortality and one of the most common type of malignant diseases worldwide. Despite remarkable progress in multimodality therapy, advanced GC with high aggressiveness always ends in treatment failure. Epithelial-mesenchymal transition (EMT) has been widely recognized to be a key process associating with GC evolution, during which cancer cells go through phenotypic variations and acquire the capability of migration and invasion. Wnt/β-catenin pathway has established itself as an EMT regulative signaling due to its maintenance of epithelial integrity as well as tight adherens junctions while mutations of its components will lead to GC initiation and diffusion. The E-cadherin/β-catenin complex plays an important role in stabilizing β-catenin at cell membrane while disruption of this compound gives rise to nuclear translocation of β-catenin, which accounts for upregulation of EMT biomarkers and unfavorable prognosis. Additionally, several microRNAs positively or negatively modify EMT by reciprocally acting with certain target genes of Wnt/β-catenin pathway in GC. Thus, this review centers on the strong associations between Wnt/β-catenin pathway and microRNAs during alteration of EMT in GC, which may induce advantageous therapeutic strategies for human gastric cancer. PMID 27082441
Am J Reprod Immunol. 2016 Mar;75(3):263-71. doi: 10.1111/aji.12470. Epub 2015 Dec 28.
MicroRNA and Embryo Implantation
Liu W1,2, Niu Z1, Li Q1, Pang RT1, Chiu PC1,3, Yeung WS1,2,3.
PROBLEM: In mammals, implantation involves interactions between an activated blastocyst and a receptive endometrium. There are controversies on the role of microRNAs in preimplantation embryo development. The actions of endometrial microRNAs on implantation are beginning to be understood. METHOD OF STUDY: Review of literature on microRNAs in preimplantation embryos and endometrium. RESULTS: Emerging evidence suggests a role of microRNAs in blastocyst activation and implantation. Differential expression of microRNAs is found between receptive and non-receptive endometria. Members of the let-7, miR-200, miR-30 families, and the miR-17-92 clusters are more commonly found to be associated with endometrial receptivity. Experimental studies show that the targets of the differentially expressed microRNAs affect endometrial receptivity, decidualization, and embryo implantation. Free and exosome/microvesicle containing microRNAs have been detected in human and ovine uterine luminal fluid (ULF). They may serve as mediators of embryo-endometrium dialog. Some observations suggest that the microRNAs in ULF may be used as biomarkers in infertility treatment. CONCLUSION: MicroRNAs in endometrium and blastocysts are involved in the implantation process. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. KEYWORDS: Endometrium; exosome; implantation; microRNA; microvesicle; preimplantation embryo
MicroRNA Profiles in Spontaneous Decidualized Menstrual Endometrium and Early Pregnancy Decidua with Successfully Implanted Embryos
Wang Y1,2, Lv Y1, Gao S3, Zhang Y3, Sun J1, Gong C1, Chen X2, Li G1.
PLoS One. 2016 Jan 6;11(1):e0143116. doi: 10.1371/journal.pone.0143116. eCollection 2016.
To comparatively analyze the human microRNA (miRNA) profiles between spontaneous decidualized menstrual endometrium and early pregnancy decidua by an in-depth sequencing of miRNAs. The specific miRNAs expressed at conception might be involved in pregnancy establishment and expression of let-7f-5p and let-7g-5p was experimentally up-regulated or inhibited to assess the effect on the expression of IGF2BP-1 and IGF2R in vitro, respectively. Samples of endometria and deciduas were obtained from 25 women who suffered from tubal or male factor subfertility and from 35 early pregnant women who underwent pregnancy termination at 6-8 weeks gestation were irrespectively collected and comparatively analyzed by miRNA sequencing and differential expression of known and novel miRNAs was analyzed using bioinformatics. The 2042 miRNA expression was analyzed in the study and the differential expression of six miRNAs was validated by qRT-PCR. The expression of four miRNAs in decidua samples was down-regulated (miR-34c, miR-92a, miR-181a-5p, and miR-191), whereas the expression of miR-10a-5p and let-7f-5p was significantly up-regulated. The expression of IGF2BP-1 and IGF2R declined and increased with overexpression and inhibition of let-7f-5p and let-7g-5p, respectively. Changes in the expression of particular miRNAs might play a role in the physiology of decidualization following successful embryo implantation, ultimately resulting in continuous decidualization. PMID 26735129
Inflammatory gene networks in term human decidual cells define a potential signature for cytokine-mediated parturition
Am J Obstet Gynecol. 2016 Feb;214(2):284.e1-284.e47. doi: 10.1016/j.ajog.2015.08.075. Epub 2015 Sep 5.
Ibrahim SA1, Ackerman WE 4th1, Summerfield TL1, Lockwood CJ1, Schatz F1, Kniss DA2.
BACKGROUND: Inflammation is a proximate mediator of preterm birth and fetal injury. During inflammation several microRNAs (22 nucleotide noncoding ribonucleic acid (RNA) molecules) are up-regulated in response to cytokines such as interleukin-1β. MicroRNAs, in most cases, fine-tune gene expression, including both up-regulation and down-regulation of their target genes. However, the role of pro- and antiinflammatory microRNAs in this process is poorly understood. OBJECTIVE: The principal goal of the work was to examine the inflammatory genomic profile of human decidual cells challenged with a proinflammatory cytokine known to be present in the setting of preterm parturition. We determined the coding (messenger RNA) and noncoding (microRNA) sequences to construct a network of interacting genes during inflammation using an in vitro model of decidual stromal cells. STUDY DESIGN: The effects of interleukin-1β exposure on mature microRNA expression were tested in human decidual cell cultures using the multiplexed NanoString platform, whereas the global inflammatory transcriptional response was measured using oligonucleotide microarrays. Differential expression of select transcripts was confirmed by quantitative real time-polymerase chain reaction. Bioinformatics tools were used to infer transcription factor activation and regulatory interactions. RESULTS: Interleukin-1β elicited up- and down-regulation of 350 and 78 nonredundant transcripts (false discovery rate < 0.1), respectively, including induction of numerous cytokines, chemokines, and other inflammatory mediators. Whereas this transcriptional response included marked changes in several microRNA gene loci, the pool of fully processed, mature microRNA was comparatively stable following a cytokine challenge. Of a total of 6 mature microRNAs identified as being differentially expressed by NanoString profiling, 2 (miR-146a and miR-155) were validated by quantitative real time-polymerase chain reaction. Using complementary bioinformatics approaches, activation of several inflammatory transcription factors could be inferred downstream of interleukin-1β based on the overall transcriptional response. Further analysis revealed that miR-146a and miR-155 both target genes involved in inflammatory signaling, including Toll-like receptor and mitogen-activated protein kinase pathways. CONCLUSION: Stimulation of decidual cells with interleukin-1β alters the expression of microRNAs that function to temper proinflammatory signaling. In this setting, some microRNAs may be involved in tissue-level inflammation during the bulk of gestation and assist in pregnancy maintenance. Copyright © 2016 Elsevier Inc. All rights reserved. KEYWORDS: inflammation; microribonucleic acid; preterm birth; systems biology; transcription factor
- Stimulation of decidual cells with interleukin-1β alters the expression of transcripts and microRNAs
- Microarray profiling of cultured decidual cells challenged with IL-1β for 6 hours revealed an up-regulation of 448 and a down-regulation of 116 transcript clusters (350 and 78 nonredundant transcripts, respectively)
- highly up-regulated transcripts were numerous proinflammatory cytokines (eg, IL-1A, IL-6, and tumor necrosis factor); leukoattractants (including 8 chemokine ligand chemokines and 6 cysteine-cysteine chemokines); interferon-inducible genes (eg, MX1, GBP1, OAS2, and IFI44); inducible prostaglandin-synthesizing enzymes (eg, prostaglandin-endoperoxide synthase 2 and prostaglandin E synthase); and matrix metalloproteinases (e.g., MMP1, MMP3, and MMP12).
- microRNAs dampen gene expression. and In addition, some miRNAs target mRNAs whose gene products exert inhibitory activity, and in this case, these miRNAs may actually enhance expression of small subsets of genes. More than 2500 unique mature human miRNAs have been identified, each with the ability to regulate the expression of potentially hundreds of genes.
- microarray data set, transcript clusters associated with 15 miRNAs and 4 long, noncoding RNAs (lncRNAs) were up-regulated by at least ±1.5-fold (false discovery rate < 0.1), whereas those corresponding to 9 miRNAs and 3 lncRNAs were down-regulated.
- Up-regulated - MiRNA 147b
MiRNA 3142 MiRNA 146a MiRNA 155, MIR155 host gene (nonprotein coding) Long intergenic nonprotein coding RNA 944 Long intergenic nonprotein coding RNA 473 Long intergenic nonprotein coding RNA 1137 MiRNA 4632 MiRNA 154 MiRNA 3182 MiRNA 4683 MiRNA 1185-1 MiRNA 645 Long intergenic nonprotein coding RNA 312 MiRNA 889 MiRNA 3614 MiRNA 299 MiRNA 4751 MiRNA 1246
MiRNA 4680 MiRNA 452, miRNA 224 MiRNA 622 MiRNA 196b Long intergenic nonprotein coding RNA 339 Long intergenic nonprotein coding RNA 478 MiRNA 143, miRNA 145, MIR143 host gene (nonprotein coding) MiRNA 424 MiRNA 503 Long intergenic nonprotein coding RNA 1085
- Based on the absolute value of the expression data, miR-21, miR-143, miR-145, and miR-4454 as well as several members of the let-7, miR-10, miR-15, miR-29, and miR-125 families were among the top 50 most highly expressed mature miRNAs in untreated term decidual cells
- whereas members of the miR-181, miR-183, and miR-200 families, which undergo down-regulation following decidualization of endometrial stromal cells,41 were among the least abundant miRNAs (data not shown).
Differentially expressed mature miRNAs in IL-1β-stimulated term decidual cells by NanoString profiling (Linear fold change was used)
- Up-regulated - miR-146a-5p, miR-525-5p
- Down regulated - miR-143-3p, miR-145-5p, miR-924, miR-4454
MicroRNA-181a is involved in the regulation of human endometrial stromal cell decidualization by inhibiting Krüppel-like factor 12
Reprod Biol Endocrinol. 2015 Mar 26;13:23. doi: 10.1186/s12958-015-0019-y.
Zhang Q1, Zhang H2, Jiang Y3, Xue B4, Diao Z5, Ding L6, Zhen X7, Sun H8, Yan G9, Hu Y10.
BACKGROUND: The transformation of endometrium into decidua is essential for normal implantation of the blastocyst. However, the post-transcriptional regulation and the miRNAs involved in decidualization remain poorly understood. Here, we examined microRNA-181a (miR-181a) expression in decidualized human endometrial stromal cell (hESC). In addition, we investigated the functional effect of miR-181a on hESC decidualization in vitro. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the profile of miR-181a in decidualized hESC. qRT-PCR, enzyme-linked fluorescent assay, and immunofluorescence assay were performed to investigate decidualization marker genes' expression after enhancing or inhibition of miR-181a expression in hESC. Luciferase reporter assay, western blotting, qRT-PCR, and immunofluorescence assay were carried out to identify the relationship between miR-181a and Krüppel-like factor 12 (KLF12). RESULTS: miR-181a expression levels increased dramatically in hESC treated with 8-Br-cAMP and MPA. Increased miR-181a expression promoted hESC decidualization-related gene expression and morphological transformation; conversely, inhibition of miR-181a expression compromised hESC decidualization in vitro. Further analysis confirmed that miR-181a interacted with the 3' untranslated region of the transcription factor KLF12 and down-regulated KLF12 at the transcriptional and translational levels. KLF12 overexpression abolished miR-181a-induced decidualization. CONCLUSIONS: Our findings suggest that miR-181a plays a functionally important role in human endometrial stromal cell decidualization in vitro by inhibiting KLF12. PMID 25889210
miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro
PLoS One. 2012;7(7):e41080. doi: 10.1371/journal.pone.0041080. Epub 2012 Jul 20.
Estella C1, Herrer I, Moreno-Moya JM, Quiñonero A, Martínez S, Pellicer A, Simón C.
Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells, which is critical for embryo implantation and pregnancy establishment. The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels, however very little is known about the post-transcriptional regulation of this process. miRNAs regulate multiple physiological pathways and their de-regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia. In this study we profile the miRNAs expression throughout human endometrial stromal (hESCs) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process. A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non-decidualized hESCs. Three miRNAs families, miR-181, miR-183 and miR-200, are down-regulated during the decidualization process. Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs. The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization. We have analyzed a battery of decidualization markers such as cell morphology, Prolactin, IGFBP-1, MPIF-1 and TIMP-3 secretion as well as HOXA10, COX2, SP1, C/EBPß and FOXO1 expression in decidualized hESCs with decreased Dicer function. We found decreased levels of HOXA10 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control. Our results provide the miRNA signature of hESC during the decidualization process in vitro. We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization. PMID 22911744
Nucleic Acids Res. 2012 Jul;40(Web Server issue):W498-504. doi: 10.1093/nar/gks494. Epub 2012 May 30.
DIANA miRPath v.2.0: investigating the combinatorial effect of microRNAs in pathways
Vlachos IS1, Kostoulas N, Vergoulis T, Georgakilas G, Reczko M, Maragkakis M, Paraskevopoulou MD, Prionidis K, Dalamagas T, Hatzigeorgiou AG.
MicroRNAs (miRNAs) are key regulators of diverse biological processes and their functional analysis has been deemed central in many research pipelines. The new version of DIANA-miRPath web server was redesigned from the ground-up. The user of DNA Intelligent Analysis (DIANA) DIANA-miRPath v2.0 can now utilize miRNA targets predicted with high accuracy based on DIANA-microT-CDS and/or experimentally verified targets from TarBase v6; combine results with merging and meta-analysis algorithms; perform hierarchical clustering of miRNAs and pathways based on their interaction levels; as well as elaborate sophisticated visualizations, such as dendrograms or miRNA versus pathway heat maps, from an intuitive and easy to use web interface. New modules enable DIANA-miRPath server to provide information regarding pathogenic single nucleotide polymorphisms (SNPs) in miRNA target sites (SNPs module) or to annotate all the predicted and experimentally validated miRNA targets in a selected molecular pathway (Reverse Search module). DIANA-miRPath v2.0 is an efficient and yet easy to use tool that can be incorporated successfully into miRNA-related analysis pipelines. It provides for the first time a series of highly specific tools for miRNA-targeted pathway analysis via a web interface and can be accessed at http://www.microrna.gr/miRPathv2.