Abstract
Mitogen-activated protein kinase (MAP kinase) pathways participate in regulation of several cellular processes involved in breast carcinogenesis. A number of non-coding RNAs including both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) regulate or being regulated by MAPKs. We performed an in-silico method for identification of MAPKs with high number of interactions with miRNAs and lncRNAs. Bioinformatics approaches revealed that MAPK14 ranked first among MAPKs. Subsequently, we identified miRNAs and lncRNAs that were predicted to be associated with MAPK14. Finally, we selected four lncRNAs with higher predicted scores (NORAD, HCG11, ZNRD1ASP and TTN-AS1) and assessed their expression in 80 breast cancer tissues and their adjacent non-cancerous tissues (ANCTs). Expressions of HCG11 and ZNRD1ASP were lower in tumoral tissues compared with ANCTs (P values < 0.0001). However, expression levels of MAPK14 and NORAD were not significantly different between breast cancer tissues and ANCTs. A significant association was detected between expression of HCG11 and estrogen receptor (ER) status in a way that tumors with up-regulation of this lncRNA were mostly ER negative (P value = 0.04). Expressions of ZNRD1ASP and HCG11 were associated with menopause age and breast feeding duration respectively (P values = 0.02 and 0.04 respectively). There was a trend towards association between ZNRD1ASP expression and patients’ age of cancer diagnosis. Finally, we detected a trend toward association between expression of NORAD and history of hormone replacement therapy (P value = 0.06). Expression of MAPK14 was significantly higher in grade 1 tumors compared with grade 2 tumors (P value = 0.02). Consequently, the current study provides evidences for association between lncRNA expressions and reproductive factors or tumor features.
Highlights
In the present investigation, we aimed at identification of MAPK-related long non-coding RNAs (lncRNAs) with putative ceRNA function
Co-expression analysis using GEPIA and Co-LncRNA tools revealed that NORAD, HCG11, ZNRD1ASP and TTN-AS1 lncRNAs co-express with MAPK14 in breast tissues
In the present study, we introduced an in silico method for identification of MAPK14-related lncRNAs with putative ceRNA role in breast cancer and assessed expression of these lncRNAs in breast cancer tissues and adjacent non-cancerous tissues (ANCTs)
Summary
In silico analyses.The total list of MAPK pathway genes were retrieved from HGNC database (https://www.genenames.org/data/genegroup/#!/group/652). The total list of MAPK pathway genes were retrieved from HGNC database The list of miRNAs identified in Homo sapiens was downloaded from Mirtarbase (http://mirtarbase.mbc.nctu.edu.tw/php/index.php) and miRNA-mRNA relationship was evaluated using this tool (based on the experimentally validated miRNA-mRNA relationship using Reporter assay and Western blotting techniques). From the obtained list of miRNA-mRNA relationship with strong evidence, those associated with MAPK genes were selected. LncBase v2 (http://carolina.imis.athena-innovation.gr/diana_tools/web/index.php?r=lncbasev2%2Findex-experimental) was used for assessment of miRNA-lncRNA associations. The identified miRNAs from the previous step were assessed in lncBase v2 and the associated lncRNAs were retrieved. Mbc.nctu.edu.tw/php/index.php) which is tool which reports these interactions based on the experimentally validated miRNA-mRNA relationship using Reporter assay and Western blotting techniques. Expression Atlas[8] data was used to identify MAPK genes with differential expression in breast cancer tissues vs normal tissues. Co-lncRNA (http://bio-bigdata.hrbmu.edu.cn/Co-LncRNA/) tool was applied to select lncRNAs which co-express with MAPK14 in breast tissues (Fig. 1)
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