Munivez, E. | bioRxiv Science

bioRxiv2024

Atrial Proteomic Profiling Reveals a Switch Towards Profibrotic Gene Expression Program in CREM-IbΔC-X Mice with Persistent Atrial Fibrillation

BackgroundOverexpression of the CREM (cAMP response element-binding modulator) isoform CREM-Ib{Delta}C-X in transgenic mice (CREM-Tg) causes the age-dependent development of spontaneous AF. PurposeTo identify key proteome signatures and biological processes accompanying the development of persistent AF through integrated proteomics and bioinformatics analysis. MethodsAtrial tissue samples from three CREM-Tg mice and three wild-type littermates were subjected to unbiased mass spectrometry-based quantitative proteomics, differential expression and pathway enrichment analysis, and protein-protein interaction (PPI) network analysis. ResultsA total of 98 differentially expressed proteins were identified. Gene ontology analysis revealed enrichment for biological processes regulating actin cytoskeleton organization and extracellular matrix (ECM) dynamics. Changes in ITGAV, FBLN5, and LCP1 were identified as being relevant to atrial fibrosis and remodeling based on expression changes, co-expression patterns, and PPI network analysis. Comparative analysis with previously published datasets revealed a shift in protein expression patterns from ion-channel and metabolic regulators in young CREM-Tg mice to profibrotic remodeling factors in older CREM-Tg mice. Furthermore, older CREM-Tg mice exhibited protein expression patterns that resembled those of humans with persistent AF. ConclusionsThis study uncovered distinct temporal changes in atrial protein expression patterns with age in CREM-Tg mice consistent with the progressive evolution of AF. Future studies into the role of the key differentially abundant proteins identified in this study in AF progression may open new therapeutic avenues to control atrial fibrosis and substrate development in AF. Graphical abstractGraphical abstract summarizing key findings of this paper. The atrial proteome in 9-month-old CREM- Tg mice with chronic persistent AF (perAF) was compared with age-matched WT littermates. In addition, proteome changes in these old CREM-Tg mice were compared with proteome changes previously identified in young CREM-Tg mice with paroxysmal AF (pAF). Moreover, an interspecies comparison was performed between old CREM-Tg mice and human patients with perAF. The major findings are that in pAF, key changes were identified in proteins involved in metabolism, energy production, DNA synthesis, and cell proliferation and growth. On the other hand, in mice and humans with perAF, key changes were found in the expression of proteins involved in collagen production, extracellular matrix remodeling, actin cytoskeleton organization, and tissue repair. O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/575097v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@603dbaorg.highwire.dtl.DTLVardef@74a168org.highwire.dtl.DTLVardef@110b834org.highwire.dtl.DTLVardef@ad96e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2021

miRNA-34c suppresses osteosarcoma progression in vivo by targeting Notch and E2F

The expression of microRNAs (miRNAs) is dysregulated in many types of cancers including osteosarcoma (OS) due to genetic and epigenetic alterations. Among these, miR-34c, an effector of tumor suppressor P53 and an upstream negative regulator of Notch signaling in osteoblast differentiation, is dysregulated in OS. Here, we demonstrated a tumor suppressive role of miR-34c in OS progression using in vitro assays and in vivo genetic mouse models. We found that miR-34c inhibits the proliferation and the invasion of metastatic OS cells, which resulted in reduction of the tumor burden and increased overall survival in an orthotopic xenograft model. Moreover, the osteoblast specific over expression of miR-34c increased survival in the osteoblast specific p53 mutant OS mouse model. We found that miR-34c regulates the transcription of several genes in Notch signaling (NOTCH1, JAG1 and HEY2) and in p53 mediated cell cycle and apoptosis (CCNE2, E2F5, E2F2 and HDAC1). More interestingly, we found that the metastatic free survival probability was increased among a patient cohort from TARGET OS which has lower expression of direct targets of miR-34c that was identified in our transcriptome analysis such as E2F5 and NOTCH1. In conclusion, we demonstrate that miR-34c is a tumor suppressive miRNA in OS progression in vivo. In addition, we highlight the therapeutic potential of targeting miR-34c in OS.

cancer biology↗