MiR-146b-5p downregulates IRAK1 and ADAM19 to suppress trophoblast proliferation, invasion and migration in miscarriage [circRNA, lincRNA, and mRNA profiles]
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ABSTRACT:
PROVIDER: PRJNA996514 | ENA |
REPOSITORIES: ENA
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Project description:A large proportion of miscarriages are classified as unexplained miscarriages (UM) since no cause is identified. No reliable biomarkers or treatments are available for these pregnancy losses. While our transcriptomic sequencing has revealed substantial upregulation of miR-146b-5p in UM villous tissues, its role and associated molecular processes have yet to be fully characterized. Our work revealed that relative to samples from normal pregnancy (NP), miR-146b-5p was significantly elevated in villous tissues from UM patients and displayed promising diagnostic potential. Moreover, miR-146b-5p agomir contributed to higher rates of embryonic resorption in ICR mice. When overexpressed in HTR-8/SVneo cells, miR-146b-5p attenuated the proliferative, invasive, and migratory activity of these cells while suppressing the expression of MMP9 and immune inflammation-associated cytokines, including IL1B, IL11, CXCL1, CXCL8, and CXCL12. Conversely, inhibition of its expression enhanced proliferation, migration, and invasion abilities. Mechanistically, IRAK1 (IL-1 receptor-associated kinase-1) and ADAM19 (a disintegrin and metalloproteinase 19) were identified as miR-146b-5p targets regulating trophoblast function, and silencing IRAK1 had similar effects as miR-146b-5p overexpression, while IRAK1 overexpression could partially reverse the inhibitory impact of this miRNA on trophoblasts. miR-146b-5p may inhibit trophoblast proliferation, migration, invasion, and implantation-associated inflammation by downregulating IRAK1 and ADAM19, participating in the pathogenesis of miscarriage and providing a critical biomarker and a promising therapeutic target for UM.
2025-01-08 | GSE237732 | GEO
Project description:A large proportion of miscarriages are classified as unexplained miscarriages (UM) since no cause is identified. No reliable biomarkers or treatments are available for these pregnancy losses. While our transcriptomic sequencing has revealed substantial upregulation of miR-146b-5p in UM villous tissues, its role and associated molecular processes have yet to be fully characterized. Our work revealed that relative to samples from normal pregnancy (NP), miR-146b-5p was significantly elevated in villous tissues from UM patients and displayed promising diagnostic potential. Moreover, miR-146b-5p agomir contributed to higher rates of embryonic resorption in ICR mice. When overexpressed in HTR-8/SVneo cells, miR-146b-5p attenuated the proliferative, invasive, and migratory activity of these cells while suppressing the expression of MMP9 and immune inflammation-associated cytokines, including IL1B, IL11, CXCL1, CXCL8, and CXCL12. Conversely, inhibition of its expression enhanced proliferation, migration, and invasion abilities. Mechanistically, IRAK1 (IL-1 receptor-associated kinase-1) and ADAM19 (a disintegrin and metalloproteinase 19) were identified as miR-146b-5p targets regulating trophoblast function, and silencing IRAK1 had similar effects as miR-146b-5p overexpression, while IRAK1 overexpression could partially reverse the inhibitory impact of this miRNA on trophoblasts. miR-146b-5p may inhibit trophoblast proliferation, migration, invasion, and implantation-associated inflammation by downregulating IRAK1 and ADAM19, participating in the pathogenesis of miscarriage and providing a critical biomarker and a promising therapeutic target for UM.
2025-01-08 | GSE237733 | GEO
Project description:miR-146b-5p downregulates IRAK1 and ADAM19 to suppress trophoblast proliferation, invasion and migration in miscarriage.
| PRJNA996510 | ENA
Project description:miR-146b-5p downregulates IRAK1 and ADAM19 to suppress trophoblast proliferation, invasion and migration in miscarriage [miRNA profiles]
| PRJNA996513 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-01-08 | GSE237734 | GEO
Project description:ADAM19 has been associated with pulmonary function traits in a number of genome wide association analyses by our group and others. We want to use a mouse model to examine the role Adam19 in lung function to clarify whether ADAM19 is truly the causal gene at this locus. We created a whole body Adam19 knockout mouse model targeting exon6 and 7 to disrupt the transcript expression from exon 8 through the end of gene sequences. In previous publications, mice lacking Adam19 exon 11, which harbor a catalytic site, were not postnatal viable. Contradictory to the previous publications, our Adam19 knockout survived postnatally. Our objectives were to determine if this novel mouse model is truly Adam19-deficient rather than a hypomorph or neomorph rescuing the previously published lethal phenotype of Adam19-deficient mice.
2024-05-10 | GSE183318 | GEO
Project description:Myelodysplastic Syndromes (MDS) result from expansion of defective hematopoietic stem/progenitor clones. There is an urgent need to develop targeted therapies capable of eliminating the defective MDS clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS-propagating clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-M-NM-:B inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is selectively detrimental to MDS clones as normal CD34+ cells are preserved. Based on conclusions derived from an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment collaboratively and selectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS. MDSL cells were transduced with lentivirus encoding shRNA targeting human IRAK1 and a negative control (pLKO) for 2.5 days. GFP positive cells were sorted for RNA extraction, labeling, and hybridization. A total of four samples were included, and two groups are assigned. Two replicates are for each group. Comparison comprises mRNA expression profile of TRAF6 knockdown (shT6) v.s. control vector (pLKO). Additionally, MDSL cells were treated with either DMSO or IRAK inhibitor for 24hrs. Cells were subjected to RNA extraction, labeling, and hybridization. A total of four samples were included, and two groups are assigned.
2013-04-25 | E-GEOD-46346 | biostudies-arrayexpress
Project description:Myelodysplastic Syndromes (MDS) result from expansion of defective hematopoietic stem/progenitor clones. There is an urgent need to develop targeted therapies capable of eliminating the defective MDS clones. We identified that IRAK1, an immune modulating kinase, is overexpressed and hyperactivated in MDS. MDS-propagating clones treated with a small-molecule IRAK1 inhibitor (IRAK1/4-Inh) exhibited impaired expansion and increased apoptosis, which coincided with TRAF6/NF-κB inhibition. Suppression of IRAK1, either by RNAi or with IRAK1/4-Inh, is selectively detrimental to MDS clones as normal CD34+ cells are preserved. Based on conclusions derived from an integrative gene expression analysis, we combined IRAK1 and BCL2 inhibitors and found that co-treatment collaboratively and selectively eliminated MDS clones. In summary, these findings implicate IRAK1 as a drugable target in MDS.
2013-04-25 | GSE46346 | GEO
Project description:Interleukin-1 receptor associated kinase 1 (IRAK1) is an important component of the IL-1R and TLR signaling pathways, which influence Th cell differentiation. Here, we show that IRAK1 promotes Th17 development by mediating IL-1β induced upregulation of IL-23R and subsequent STAT3 phosphorylation, thus enabling sustained IL-17 production. Moreover, we show that IRAK1 signaling fosters Th1 differentiation by mediating T-bet induction and counteracts Treg generation. Cotransfer experiments revealed that Irak1-deficient CD4+ T cells have a cell-intrinsic defect in generating Th1 and Th17 cells under inflammatory conditions in spleen, mesenteric lymph nodes and colon tissue. Furthermore, IRAK1 expression in T cells was shown to be essential for T cell accumulation in the inflamed intestine and mLNs. Transcriptome analysis ex vivo revealed that IRAK1 promotes T cell activation and induction of gut-homing molecules in a cell-intrinsic manner. Accordingly, Irak1-deficient T cells failed to upregulate surface expression of α4β7 integrin after transfer into Rag1-/- mice and their ability to induce colitis was greatly impaired. Lack of IRAK1 in recipient mice provided additional protection from colitis. Therefore, IRAK1 plays an important role in intestinal inflammation by mediating T cell activation, differentiation and their accumulation in the gut. Thus, IRAK1 is a promising novel target for therapy of inflammatory bowel diseases.
2015-11-13 | GSE73875 | GEO
Project description:MicroRNA Predictors of Miscarriage
| PRJNA877004 | ENA