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Malignant transformation of fallopian tube secretory epithelial cells (FTSECs) is a key contributing event to the development of high-grade serous ovarian carcinoma (HGSOC). Our recent findings implicate oncogenic transformative events in chronic iron-exposed FTSECs, including increased expression of oncogenic mediators, increased telomerase transcripts, and increased growth/migratory potential. Herein, we extend these studies by implementing an integrated transcriptomic and mass spectrometry-based proteomics approach to identify global miRNA and protein alterations, for which we also investigate a subset of these targets to iron-induced functional alterations. Proteomic analysis identified > 4500 proteins, of which 243 targets were differentially expressed. Sixty-five differentially expressed miRNAs were identified, of which 35 were associated with the "top" proteomic molecules (> fourfold change) identified by Ingenuity Pathway Analysis. Twenty of these 35 miRNAs are at the 14q32 locus (encoding a cluster of 54 miRNAs) with potential to be regulated by DNA methylation and histone deacetylation. At 14q32, miR-432-5p and miR-127-3p were ~ 100-fold downregulated whereas miR-138-5p was 16-fold downregulated at 3p21 in chronic iron-exposed FTSECs. Combinatorial treatment with methyltransferase and deacetylation inhibitors reversed expression of these miRNAs, suggesting chronic iron exposure alters miRNA expression via epigenetic alterations. In addition, PAX8, an important target in HGSOC and a potential miRNA target (from IPA) was epigenetically deregulated in iron-exposed FTSECs. However, both PAX8 and ALDH1A2 (another IPA-predicted target) were experimentally identified to be independently regulated by these miRNAs although TERT RNA was partially regulated by miR-138-5p. Interestingly, overexpression of miR-432-5p diminished cell numbers induced by long-term iron exposure in FTSECs. Collectively, our global profiling approaches uncovered patterns of miRNA and proteomic alterations that may be regulated by genome-wide epigenetic alterations and contribute to functional alterations induced by chronic iron exposure in FTSECs. This study may provide a platform to identify future biomarkers for early ovarian cancer detection and new targets for therapy.
Pubmed ID: 33737539
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Central online repository for microRNA nomenclature, sequence data, annotation and target prediction.Collection of published miRNA sequences and annotation.
View all literature mentionsPrivately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.
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View all literature mentionsProteintech Europe Ltd is an ISO 9001:2008 certified company
View all literature mentionsA quantitative proteomics software package for analyzing large-scale mass-spectrometric data sets. It is a set of algorithms that include peak detection and scoring of peptides, mass calibration, database searches for protein identification, protein quantification, and provides summary statistics.
View all literature mentionsGenomatix is a privately held company that offers software, databases, and services aimed at understanding gene regulation at the molecular level representing a central part of systems biology. Its multilayer integrative approach is a working implementation of systems biology principles. Genomatix combines sequence analysis, functional promoter analysis, proprietary genome annotation, promoter sequence databases, comparative genomics, scientific literature data mining, pathway databases, biological network databases, pathway analysis, network analysis, and expression profiling into working solutions and pipelines. It also enables better understanding of biological mechanisms under different conditions and stimuli in the biological context of your data. Some of Genomatix'' most valuable assets are the strong scientific background and the years of experience in research & discovery as well as in development & application of scientific software. Their firsthand knowledge of all the complexities involved in the in-silico analysis of biological data makes them a first-rate partner for all scientific projects involving the evaluation of gene regulatory mechanisms. The Genomatix team has more than a decade of scientific expertise in the successful application of computer aided analysis of gene regulatory networks, which is reflected by more than 150 peer reviewed scientific publications from Genomatix'' scientists More than 35,000 researchers in industry and academia around the world use this technology. The software available in Genomatix are: - GenomatixSuite: GenomatixSuite is our comprehensive software bundle including ElDorado, Gene2Promoter, GEMS Launcher, MatInspector and MatBase. GenomatixSuite PE also includes BiblioSphere Pathway Edition. Chromatin IP Software - RegionMiner: Fast, extensive analysis of genomic regions. - ChipInspector: Discover the real power of your microarray data. Genome Annotation Software - ElDorado: Extended Genome Annotation. - Gene2Promoter: Retrieve & analyze promoters - GPD: The Genomatix Promoter Database, which is now included with Gene2Promoter. Knowledge Mining Software - BiblioSpere : The next level of pathway/genomics analysis. - LitInspector: Literature and pathway analysis for free. Sequence Analysis Software - GEMS Launcher: Our integrated collection of sequence analysis tools. - MalInspector: Search transcription factor binding sites - MatBase: The transcription factor knowledge base. Other (no registration required) Software - DiAlign: Multiple alignment of DNA/protein sequence. - Genomatix tools: Various small tools for sequence statistics, extraction, formatting, etc.
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