Co-expression network analysis reveals mir-182-5p as a biomarker which alter rap1 and mapk signaling pathways in prostate cancer (pc)

Shadi Mahdipour,1 Masoumeh sepahvand,2 Pouya salehipour,3 Mojdeh mahdiannasser,4,*

1. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
2. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
3. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
4. Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Introduction

Circulating micrornas (mirnas) have provided an active and swiftly evolving region of common research that has a potential to improve cancer diagnostics and therapeutics. especially, mirnas could provide potential new biomarkers for prostate cancer (pc), one of the most common malignant tumors in men. common diagnostic tests for prostate cancer have low specificity and poor sensitivity. despite of the fact that many cases of prostate cancer are slow growing and therefore, do not impose a major effect on health, there are no specific tests that can differentiate these from cancers that will become aggressive and life-threatening. circulating mirnas are highly stable molecules and are detectable and quantifiable in a range of biofluids, so they could be potential diagnostic, prognostic and predictive biomarkers. deregulation of mirnas is involved in promoting cell proliferation and preventing apoptosis, which contributes to the pathogenesis of cancer. the relevance of mirna regulation in the induction of cancer can be tracked by analyzing mirna targeted genes. to recognize conserved mirna-mrna interactions in cancer, we have carried out an integrative analysis of transcriptomic data. we analyzed 491 samples of pc using tcga-coad data along with co-expression analysis of mirnas, lncrnas, and mrnas.

Methods

Transcriptome profiling data of 491 pc primary tumors and 51 primary normal samples were extracted from the tcga-coad project. differential expression analysis and co-expression network analysis among mrnas, mirnas, and lncrnas were performed to create network pathways that reveal an active mirna. for mirna analysis, we employed mirtarbase database to find experimental targets of mirna. in addition, to find the functions of mirna, gene pathway enrichment was performed by network analysis of identified mrnas using kegg and string databases.

Results

We identified hsa-mir-182-5p as a candidate mirna biomarker that was up-regulated in pc. mir-182-5p was highly differentiated with a log2fc of -2.570 and a p-value of 3.867e-21. however, no significant difference was observed between tumor and metastatic tumor samples. network analysis determined that mir-182-5p was associated with rap1 signaling pathway (adjusted p-value= 6.84e-14) by altering the expression of gnao1, met, rap1a, tiam1, adcy6, calm1, efna5, fgf9, fgfr2, mras, rras, and tln1, also was associated with mapk signaling pathway (adjusted p-value= 3.34e-13) by altering the expression of rap1a, bdnf, fgf9, fgfr2, map3k2, map3k3, mras, mef2c, ppp3cb, rras, srf,and tgfbr2.

Conclusion

Mirna variation might contribute to human tumorgenesis. investigation of differentially expressed mirnas in tumor samples has yielded important information on tumorgenesis. an understanding of the molecular pathways involved in pc tumorgenesis would improve the diagnosis and treatment of the disease. we screened 542 pc and normal samples, using tcga-coad data, and identified hsa-mir-182-5p that was up-regulated in tumor samples. this conclusion suggests that mir-182-5p could be a potential biomarker for pc. mir-182-5p is over-expressed throughout prostate cancer progression and might be useful as a prognostic biomarker. similarly, several other studies have suggested that mir-182-5p expression is significantly higher in prostate cancer compared to normal samples even though pathway analysis has not been carried out. subsequently, we identified target genes of mir-182-5p using mirtarbase database. the results of pathway analysis suggest the involvement of this mirna in the regulation of biologically important signaling cascades, including rap1 signaling and mapk signaling. deregulation of these pathways is likely to have a major effect on several aspects of prostate cancer biology. the results of our study suggest that mir-182-5p may play a significant role in these processes. in different cellular contexts, one mirna can probably modulate different pathways and cause various phenotypes depending on the availability of a certain population of mrna targets. this study showed that several number of target genes are associated with rap1 and mapk signaling pathways. since signaling pathways are highly controlled, any changes in the genes involved in these pathways may lead to the initiation or progression of cancer. analysis of mirna expression and recognition of target genes may provide an understanding of potential tumorgenic mechanisms in pc. further study to identify the targets of mirnas will increase our understanding of their mechanism and improve our ability to utilize them clinically as biomarkers or as therapeutic targets. in addition, the molecular mechanisms of mir-182 and its function in different tissues remain unclear and should be considered in future studies.

Keywords

Co-expression network analysis, biomarker, signaling pathways, prostate cancer