Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Direct targeting of SLC7A11 by miR-143-3p promotes ferroptosis and suppresses malignancy in cervical squamous cell carcinoma

ABSTRACT: We performed RNA sequencing (RNA-seq) on cervical tissues from 3 patients with SCC (IB stage, HPV16-positive) and 3 normal controls (HPV16-negative). Differential gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were conducted to screen key microRNAs (miRNAs) and target genes. Expression of miR-143-3p and SLC7A11 in SCC and normal control tissues was determined by quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemical staining, and Western blotting (WB). Furthermore, the effect of miR-143-3p mimics and inhibitors on cell proliferation and ferroptosis was evaluated via Cell Counting Kit (CCK)-8 and scratch assays, along with WB, while concurrently detecting ferroptosis-related biochemical markers. Finally, the role of miR-143-3p in epithelial-mesenchymal transition (EMT) of cervical cancer cells was evaluated by WB and immunofluorescence.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Cervus nippon

SUBMITTER: Jingwen Meng

PROVIDER: E-MTAB-17403 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Retinal neovascularization is a severe complication of several neovascular retinal diseases, including proliferative diabetic retinopathy, central retinal vein occlusion and retinopathy of prematurity. MicroRNAs (miRNAs) are master regulators of gene expression that play an important role in retinal neovascularization. Here, we investigate the retinal miRNA expression profile in a rat model of oxygen-induced retinopathy (OIR) using miRNA-Seq. We show that miR-143-3p, miR-126-3p, and miR-150-5p are significantly downregulated in the retina of OIR rats, and intravitreal injection of synthetic mimics of these miRNAs significantly ameliorate retinal neovascularization in this animal model. Of these identified miRNAs, miR-143 which is highly expressed in the neural retina and retinal vasculature is here identified for the first time to be associated with retinal neovascularization. With a focus on miR-143 expression in primary human retinal endothelial cells, we explore its involved pathways through a multi-omics analysis. In miR-143 treated cells, the functional evaluation showed a decrease in cell migration and delayed endothelial vessel-like tube remodelling. Consequently, the multi-omics analysis suggests that miR-143 negatively impacts endothelial cell activity through regulating cell-matrix adhesion and mediating HIF signalling pathway. Furthermore, using cytoHubba, a topological analysis method to assess the essentiality of genes, we predict 20 top hub genes regulated by miR-143 that may be involved in mediating endothelial cell function. Using CIBERSORTx, a bulk gene expression deconvolution algorithm, we analyze a public RNA-Seq dataset (GSE102485) and demonstrate that the retinal neovascular membranes in patients with proliferative diabetic retinopathy (PDR) principally consist of endothelial cells. We then identify 2 hub genes, THBS1 and SERPINE1, direct targets of miR-143, which on further analysis demonstrate an expression level significantly altered in the PDR patients compared to controls. These findings suggest that miR-143 appears to be essential for limiting endothelial cell-matrix adhesion, thus suppressing retinal neovascularization. The present study might have important implications for the exploration of potential therapeutic targets for the treatment of neovascular ocular diseases.

Project description:<p>Introduction: Cervical cancer is the fourth most common malignancy in women and is primarily caused by persistent infection with high-risk human papillomavirus (HPV). In addition, host immune responses, genetic factors, and lifestyle habits also have etiological roles. The cervicovaginal microbiome undergoes dynamic changes during menopause, which may be involved in the progression of cervical neoplasia. We aimed to elucidate the association between cervical microenvironmental changes and the progression of cervical neoplasia before and after menopause by integrating analyses of the cervical microbiome, related metabolites, cytokines, and microRNAs. Methods: A total of 248 HPV-positive women with cervical neoplasia, including 17 with cervical intraepithelial neoplasia (CIN1), 80 with CIN2, 82 with CIN3, and 69 with squamous cell carcinoma (SCC), were enrolled. As normal controls, 48 HPV-negative healthy women were included. Each group was stratified based on the mean menopausal age of 50 years. Cervical mucus was analyzed according to the methods outlined below. The microbiota was profiled by 16S rRNA gene sequencing, metabolites were analyzed by ultra-HPLC-tandem mass spectrometry, RT-qPCR was used for miRNA expression analysis, and RANTES levels were quantified by multiplex bead array. Data analysis was performed using MicrobiomeAnalyst and MetaboAnalyst.Results: In the SCC group, Prevotella and Atopobium were the key bacterial genera among the younger group, while Peptoniphilus, Fusobacterium, and Porphyromonas were more prevalent in elderly group (LDA score > 4.5). We observed a consistent positive correlation between Atopobium and xanthine in younger groups with CIN2 or worse (p < 0.0001). However, no such correlations were detected in elderly women. In addition, Atopobium, Adlercreutzia, and Gardnerella showed significant positive correlation with nicotinic acid in younger women with SCC compared to the elderly women (p < 0.0001). In the younger SCC women, several metabolites were significantly elevated in groups with high expression levels of RANTES, miR-20b-5p, and miR-155-5p.The cervical microbiome undergoes changes during menopause, and may influence disease progression by interacting with metabolites, cytokines, and miRNAs. These results highlight the potential for personalized medicine for cervical cancer that is tailored to different age groups.Please update the study abstract/description</p>

Project description:Cervical cancer results from the accumulation of (epi)genetic aberrations following persistent infection with high-risk human papillomavirus (HPV). In order to define genetic aberrations associated with cervical carcinogenesis, chromosomal profiles of high-grade cervical intraepithelial neoplasia (CIN) were generated. Common aberrations usually encompass large genomic regions and contain numerous genes, hampering identification of actual driver genes. Consequently, direct evidence of chromosomal alterations actively contributing to cervical carcinogenesis has been lacking so far. By analyzing 60 high-grade CIN with high resolution arrayCGH we identified focal chromosomal aberrations that each harbour only one or a few genes. In total 74 focal aberrations were identified encoding 305 genes. Analysis of genes located within these focal aberrations, using two independent expression microarray datasets, revealed concurrent altered expression in high-grade CIN and/or cervical carcinomas compared to normal cervical samples for 8 genes: ATP13A3, HES1, OPA1, HRASLS, EYA2, ZMYND8, APOBEC2 and NCR2. Gene silencing of EYA2, located within a focal gain at 20q13, significantly reduced viability and migratory capacity of HPV16-transformed keratinocytes. Interestingly, for hsa-miR-375, located within the most frequently identified focal loss at 2q35, a direct correlation between a (focal) loss and significantly reduced expression was found. Down-regulation of hsa-miR-375 expression during cervical carcinogenesis was confirmed in a second independent series of cervical tissues. Moreover, ectopic expression of hsa-miR-375 in 2 cervical carcinoma cell lines reduced cellular viability. In conclusion, our data provide a proof of concept that chromosomal aberrations are actively contributing to HPV-induced carcinogenesis and identify EYA2 and hsa-mir-375 as oncogene and tumor suppressor gene, respectively. DNA from microdissected tissues: 60 samples total. 11 high-grade CIN, <5yr preceding hrHPV infection, 43 high-grade CIN >5yr preceding hrHPV infection, 6 CIN3 adjacent to SCC

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Direct targeting of SLC7A11 by miR-143-3p promotes ferroptosis and suppresses malignancy in cervical squamous cell carcinoma

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