Dataset Information

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

ABSTRACT:

Purpose

MiRNAs are small noncoding RNAs that have been implicated in tumor development. They regulate target gene expression either by mRNA degradation or by translation repression. Activation of β-catenin has been linked to pterygium progression. Here, we hypothesize that β-catenin-associated miRNA, miRNA-221, and downstream p27Kip1 gene expression are correlated with the pathogenesis of pterygium.

Methods

We collected 120 pterygial and 120 normal conjunctival samples for this study. Immunohistochemistry and real-time reverse transcription (RT)-PCR were performed to determine β-catenin protein localization, miR-221, and p27Kip1 gene expression. Pterygium cell line (PECs) cell models were used to confirm the effect of β-catenin, miR-221, and p27Kip1 gene in the proliferation of pterygium cells.

Results

Seventy-two (60.0%) pterygial specimens showed high miR-221 expression levels, which was significantly higher than the control groups (13 of 120, 10.8%, p<0.0001). MiR-221 expression was significantly higher in β-catenin-nuclear/cytoplasmic-positive groups than in β-catenin membrane-positive and negative groups (p=0.001). We also found that p27Kip1 gene expression in pterygium was negatively correlated with miR-221 expression (p=0.002). In the clinical association, miR-221 expression was significantly higher in the fleshy and intermediate groups than in the atrophic group (p=0.007). The association of miR-221, p27Kip1 and proliferation of pterygium were also confirmed in the PECs model.

Conclusions

Our study demonstrated that activation of β-catenin in pterygium may interact with miR-221, resulting in p27Kip1 gene downregulation that influences pterygium pathogenesis.

SUBMITTER: Wu CW

PROVIDER: S-EPMC4105113 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

Wu Chueh-Wei CW Cheng Ya-Wen YW Hsu Nan-Yung NY Yeh Ken-Tu KT Tsai Yi-Yu YY Chiang Chun-Chi CC Wang Wei-Ran WR Tung Jai-Nien JN

Molecular vision 20140721

<h4>Purpose</h4>MiRNAs are small noncoding RNAs that have been implicated in tumor development. They regulate target gene expression either by mRNA degradation or by translation repression. Activation of β-catenin has been linked to pterygium progression. Here, we hypothesize that β-catenin-associated miRNA, miRNA-221, and downstream p27Kip1 gene expression are correlated with the pathogenesis of pterygium.<h4>Methods</h4>We collected 120 pterygial and 120 normal conjunctival samples for this st ...[more]

PMID: 25053875

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Project description:Cyclooxygenase (COX)-, lipoxygenase (LOX)-, and cytochrome P450 monooxygenase (CYP)-derived eicosanoids have been implicated in ocular surface inflammation and neovascularization. These eicosanoids are subjected to regulation by enzymes, such as heme oxygenases (HOs) and ferritin.Quantitative polymerase chain reaction and lipidomics based on liquid chromatography-tandem mass spectrometry were performed on pterygia from patients undergoing surgical pterygium excision. Control tissues consisted of donor corneas. In addition, lipidomics based on liquid chromatography-tandem mass spectrometry was performed on tears collected from patients before the surgery.Messenger RNA (mRNA) expression of HO-2, the constitutive HO isoform, was upregulated by 40% in pterygia compared with control tissue, whereas the mRNA level of the inducible form, HO-1, was downregulated by more than 50%. Levels of CYP4B1 mRNA showed an approximate 2-fold increase in pterygia compared with control. Lipidomic analysis of tissues indicated a moderate elevation in Prostaglandin E2 and thromboxane B2 levels in pterygia compared with control. Among the LOX-derived metabolites, the antiinflammatory-hydroxyeicosatetraenoic acid (15-HETE) levels were significantly reduced in pterygia (79.3 ± 48.11 pg/mg protein) compared with control (586.2 ± 213.5 pg/mg protein), whereas the proinflammatory LOX- and CYP4B1-derived 12-HETE levels were 10-fold higher in pterygia (2768 ± 832.3 pg/mg protein) compared with control (231.4 ± 87.35 pg/mg protein). Prostaglandin E2 and HETEs were also present in tears from patients with pterygium but were not detected in tears from healthy volunteers. The mRNA expression levels of both light and heavy chain ferritin were 60% and 30% lower, respectively, in pterygia compared with control.We believe that a dysfunctional HO-ferritin system leads to increased levels of proinflammatory mediators, thus contributing to the inflammation characteristic of pterygia.

Project description:BackgroundPterygium is an ocular surface disease that can cause visual impairment if it progressively invades the cornea. Although many pieces of research showed ultraviolet radiation is a trigger of pterygium pathological progress, the underlying mechanism in pterygium remains indistinct.MethodsIn this study, we used microarray to evaluate the changes of transcripts between primary pterygium and adjacent normal conjunctiva samples in China. Then, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analyses. Moreover, we constructed protein-protein interaction (PPI) and miRNA-mRNA regulatory networks to predict possible regulatory relationships. We next performed gene set enrichment analysis (GSEA) to explore the similarities and differences of transcripts between Asian studies from the Gene Expression Omnibus database. Furthermore, we took the intersection of differentially expressed genes (DEGs) with other data and identified hub genes of the development of pterygium. Finally, we utilized real-time quantitative PCR to verify the expression levels of candidate genes.ResultsA total of 49 DEGs were identified. The enrichment analyses of DEGs showed that pathways such as the Wnt-signaling pathway and metabolism-related pathways were upregulated, while pathways such as hormone-related and transcription factor-associated pathways were downregulated. The PPI and miRNA-mRNA regulatory networks provide ideas for future research directions. The GSEA of selecting Asian data revealed that epithelial-mesenchymal transition and myogenesis existed in the pathology of pterygium in the Asian group. Furthermore, five gene sets (interferon-gamma response, Wnt beta-catenin signaling, oxidative phosphorylation, DNA repair, and MYC targets v2) were found only in our Chinese datasets. After taking an intersection between selecting datasets, we identified two upregulated (SPP1 and MYH11) and five downregulated (ATF3, FOS, EGR1, FOSB, and NR4A2) hub genes. We finally chose night genes to verify their expression levels, including the other two genes (SFRP2 and SFRP4) involved in Wnt signaling; Their expression levels were significantly different between pterygium and conjunctiva.ConclusionsWe consider hormone-related, metabolic, and Wnt signaling pathways may be important in the pathology of pterygium development. Nine candidate genes we identified deserve further study and can be potential therapeutic targets.

Dataset Information

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

Purpose

Methods

Results

Conclusions

Publications

MiRNA-221 negatively regulated downstream p27Kip1 gene expression involvement in pterygium pathogenesis.

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