Co-expression network analysis reveals biomarker mirnas and their functions in colorectal cancer (crc)

Pouya Salehipour,1 Shadi mahdipour,2 Masoumeh sepahvand,3 Zahra bahmanpoor,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, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Introduction

Colorectal cancer (crc) is the third most common type of cancer worldwide and a leading cause of cancer death. as a result, vigorous effort has been made to find effective therapeutic strategies such as those on the basis of etiology. regarding this matter, various mirnas have been shown to associate with crc. in order to identify corresponding mirnas, several approaches can be applied including whole genome studies, and co-expression analysis among mirnas, lncrnas, and mrnas. finding these mirnas and their target genes facilitates the recognition of the signaling pathways in which they attend, and therefore, provide a promising therapeutic outcome. the significance of mirnas is well-defined regarding their role in the initiation and progression of crc as well as their diagnostic, prognostic, and predictive use as biomarkers. an exact knowledge of crc-specific mirnas, their interactions with genes and rnas, as well as regulation and deregulation mechanisms, is a potentially effective strategy to both improve current therapeutic approaches and help us find new ones. this study was designed to achieve this goal by analyzing 445 samples of crc using tcga-coad data along with co-expression analysis of mirnas, lncrnas, and mrnas.

Methods

Transcriptome profiling data of 445 crc primary tumors and 8 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 active mirnas. in addition, experimental targets of these mirnas were determined by mirtarbase database. to find the functions of these mirnas in crc, nested network analysis of identified mrnas was performed using kegg and string databases to identify altered signaling pathways in crc.

Results

Two mirnas, hsa-mir-141-3p and hsa-mir-194-5p, were identified as candidate mirna biomarkers in crc. both mirnas were up-regulated in crc. however, mir-141-3p was highly differentiated with a log2fc of -4.762 and a p-value of 1.297e-10. network analysis determined that mir-141-3p was associated with hippo signaling pathway (adjusted p-value= 7.10e-04) by altering the expression of stk3, tgfb2, yap1, tcf7l1, gli2, and ywhag genes, and with pi3k-akt signaling pathway (adjusted p-value= 1.70e-02) by altering the expression of reln, eif4e, pten, phlpp1, phlpp2, and ywhag genes. in addition, mir-194-5p was associated with wnt signaling pathway (adjusted p-value= 1.90e-01) by altering the expression of rbx1, prickle1, and sox17 genes.

Conclusion

Deregulation of mirnas is a prevalent phenomenon in many types of cancer and occurs due to deletion or amplification of mirna encoding genes, abnormal transcriptional control, epigenetic changes, and aberrant mirna biogenesis. mirnas have been constantly reported as potential biomarkers in cancer that can serve as diagnostic, prognostic and therapeutic tools as well as targets. in the current experiment, we suggested a strategy to find mirnas that can serve as candidate biomarkers in crc. our results revealed that hsa-mir-141-3p and hsa-mir-194-5p are potential biomarkers in this type of cancer. mir-141 is an iconic mirna, which is reported to be up-regulated in crc. mir-141 promotes cell proliferation by targeting other genes such as sip1, or through inhibition of map2k4. genes involved in cell signaling comprise a major group of targets for mirnas. as for mir-141, a noticeable number of target genes are associated with signaling pathways: stk3, tgfb2, yap1, tcf7l1, gli2, and ywhag in hippo pathways and reln, eif4e, pten, phlpp1, phlpp2, and ywhag genes in pi3k-akt pathway. since signaling pathways are tightly regulated and controlled, any alteration in the genes that are involved in these pathways, such as mir-141 gene, would further affect cell signaling and lead to initiation or progression of cancer. finding other mirnas with similar contribution is an important step in the recognition of signaling pathways linked to different types of cancer, which also guides us through the path of finding improved and more effective therapeutics.

Keywords

Colorectal cancer (crc), mir-141-3p, mir-194-55, co-expression network analysis, signaling pathways