BackgroundColorectal cancer is the life-threatening tumor with both high prevalence and mortality worldwide. However, the molecular mechanism behind it remains unknown. Methods: Herein, the potential prognostic candidate biomarkers for colorectal cancer were tested by Bioinformatical analysis combined with the CRC clinical samples. Three data sets (GSE32323, GSE44076 and GSE43078) were collected from the gene expression omnibus (GEO). The limma and clusterProfifiler packages were used to identify differentially expressed genes (DEGs) and conduct functional enrichment analysis, respectively. To retrieve Interacting Genes (STRING) database, protein–protein interaction (PPI) network was built up using Search Tool, and Cytoscape was applied to carry out the module analysis. Subsequently, the online tool GEPIA was employed to conduct overall survival analysis (http://gepia.cancer-pku.cn/index.html), and the Oncomine database was used to analyze prognostic candidate biomarkers. Finally, 4 key hub genes were selected for validation of their expression levels in 9 patients newly diagnosed with CRC via reverse transcription‑quantitative PCR (RT‑qPCR). To evaluate the accuracy of prediction, time-dependent receiver operating characteristic (ROC) was applied.ResultsIn total, 547 DEGs got identifified, inclusive of 475 downregulated and 72 upregulated genes with a signifificant enrichment in the cellular response to hypoxia, the positive control of ERK1 and ERK2 cascade and the positive control of apoptotic process. The enhanced pathways were Pathways in cancer,PI3K-Akt signaling pathway,cGMP-PKG signaling pathway. Through the extraction of critical modules from the PPI network, 10 hub genes got removed. These 10 hub genes are all up-regulated genes and are highly expressed in colorectal cancer. Survival analysis shows that only CCNB1 and CCNA2 are associated with the survival prediction of colorectal cancer. Moreover, consistence is show between the TCGA data sets and the expression levels of the 4 hub genes. Receiver Operating Characteristic(ROC) curves showed that all CCNB1,CCNA2,AURKA and BUB1B have potential predictive value.Briely, new hub genes identifified can shed light on the underlying mechanism behind CRC carcinogenesis and development, which is coducive to detecting and treating CRC timely.