Meta And Bioinformatics Analysis Of The Prognostic Value Of MiR-204-5p In Cancer

Objective:MiR-204-5p(previous ID: miR-204)is located in the q21.12 region of chromosome 9 and is absent in many types of cancers.It is directly related to the proliferation,invasion,drug resistance,epithelial-mesenchymal transformation and related signal pathway disorders of malignant tumors.Recently,there have been many reports on the association between miR-204-5p and cancer.However,its prognostic evaluation and functional role in various types of cancer has not been clearly defined.Considering that miR-204-5p and its target genes may be important markers for prognosis evaluation and therapeutic targets of cancer,this paper carried out a systematic meta-analysis to clarify miR-204-5p prognostic value in cancer,bioinformatics analysis to explore its mechanism in cancer.Moreover,key cancer target genes were predicted to further explore the prognostic value and functional role of target genes in cancer.This study provides evidence for miR-204-5p and its target genes as novel tumor markers and therapeutic targets.Methods:1.Retrieval of the studies on the relationship between miR-204-5p expression and survival in cancer patients published before April 22,2020 in Pub Med,Embase,Cochrane Library,VIP,Wanfang and CNKI.The hazard ratio(HR)and 95% confidence interval(CI)of overall survival(OS),disease-free survival(DFS)and recurrence-free survival(RFS)were used to evaluate the effect of miR-204-5p expression on the prognosis of patients.Rev Man 5.3 and STATA 16.0 were used for data merging and publication bias test,respectively.2.The target gene set of miR-204-5p was predicted by five target gene prediction databases of Target Scan7.2,miRDB,miRTar Base,micro T-CDS and miRWalk3.0.The target gene set was introduced into STRING database to establish protein interaction network.The significant module target genes were extracted by MCODE and the top 50 central target genes were extracted by cytohubba for functional enrichment analysis,respectively.3.The differentially expressed gene chips of two groups of gastric cancer(GC)and paracancerous tissues were screened from GEO database: GSE19826 and GSE26899.Through GEO2 R analysis,901 up-regulated genes in gastric cancer were selected and intersected with central target genes,and 10 key target genes up-regulated by miR-204-5p in gastric cancer were screened.4.Prognostic analysis of key target genes by Kaplan Meier-plotter platform.Results:1.16 articles reported OS statistics on the log-rank test.Through the merger strategy,we determined that the reduction of miR-204-5p expression was related with poor prognosis.Subgroup analysis manifested that miR-204-5p was more significantly associated with poor prognosis in tissue samples,sample size greater than or equal to one hundred,and gastrointestinal cancer,non-small cell lung cancer(NSCLC),head and neck squamous cell carcinoma samples with combined HR(low expression : high expression)of 2.17,2.47,1.64,1.70,and 2.63,respectively.2.7 articles reported OS statistics on the multivariate cox regression analysis.The combined HR manifested that miR-204-5p was obvious correlated with OS in blood and GC samples with combined HR(low expression :high expression)of 1.72,and 1.81,respectively.However,the heterogeneity in gastric cancer specimens was 51%.The results were not stable enough.3.3 studies reported DFS/RFS statistics on the log-rank test.The combined HR(low expression :high expression;HR=2.48)manifested that the low expression of miR-204-5p in both tissue and blood samples was significantly associated with poor DFS/RFS in cancer patients.4.2 studies reported the association between miR-204-5p combined with other micro RNAs expression and OS(low expression :high expression;HR =1.69),and the corresponding significance was also significant(P = 0.02).However,due to the small number of articles,the results were significantly heterogeneous(I~2 = 67.80%,P = 0.078).It leads to the lack of reliability of the experimental results.5.The functional enrichment analysis of significant target genes showed that miR-204-5p target genes were mainly involved in ubiquitin protease activity and other related molecular functions,as well as ubiquitin-mediated cell hydrolysis signal pathway.Secondly,functional enrichment analysis of central target gene showed that miR-204-5p target gene was involved in neurotrophin signal pathway,c AMP signal pathway,axon guidance,renal cell carcinoma,pancreatic cancer,colorectal cancer and other cancer pathways.In addition,it was also involved in gastric cancer-related signal pathways,such as Fox O signal pathway,PI3K-Akt signal pathway,Ras signal pathway,Hippo signal pathway,Erb B signal pathway,Rap1 signal pathway,and so on.6.901 genes differentially expressed in gastric cancer and paracancerous tissues were screened by GSE19826 and GSE26899 microarray,and 10 target genes regulated by miR-204-5p in gastric cancer were found by intersecting with central target genes.Survival analysis showed that 8 target genes were significant for the prognosis of patients with gastric cancer,including STC2?SPARC?SOD2?SERPINE1?EPHB2?EPHB1?HRH4 and IL11?Conclusion:1.Our meta-analysis showed that with the median or average as the threshold,the overexpression of miR-204-5p can be a protective factor for gastrointestinal cancer,NSCLC and head and neck squamous cell carcinoma.The relatively low expression of miR-204-5p is significantly correlated with the reduced survival rate of patients with gastrointestinal cancer,NSCLC and head and neck squamous cell carcinoma,and the low expression of miR-204-5p in blood may be used as an independent prognostic indicator of gastric cancer.The low expression of miR-204-5p in blood and tissue is associated with higher recurrence rate and shorter disease-free survival time in cancer patients.2.Bioinformatics analysis shows that the central target gene of miR-204-5p is mainly involved in PI3K-Akt and Ras signal pathways,and activates PI3K/Akt/m TOR and Ras/Raf/MEK/ERK carcinogenic signal pathways to enhance the growth,survival and metabolism of cancer cells.3.Eight target genes regulated by miR-204-5p in gastric cancer were found by GEO database and Kaplan Meier-plotter survival analysis.Among them,the high expression of SOD2,STC2 and SPARC can lead to lymph node metastasis and poor clinical stage in patients with gastric cancer,which can be used as independent prognostic indicators of gastric cancer;the high expression of SERPINE1,EPHB2 and SOD2 can promote the proliferation and invasion of gastric cancer cells and can be used as prognostic markers of gastric cancer;there is insufficient evidence about the prognostic role of EPHB1,HRH4 and IL11 in gastric cancer,and further studies are needed to verify their prognostic value.4.SOD2 can play a carcinogenic role through Fox O signaling pathway;SERPINE1can play a carcinogenic role through Hippo signaling pathway;EPHB1 and EPHB2 can play a carcinogenic role through axon-guided cancer-related signaling pathways,providing targets for accurate treatment of gastric cancer.