Colorectal cancer (CRC) is the second most deadly cancer in the whole world, with the underlying mechanisms largely indistinct. Therefore, we aimed to identify significant pathways and genes involved in the initiation, formation and poor prognosis of CRC using bioinformatics methods. In this study, we compared gene expression profiles of CRC cases with those from normal colorectal tissues from three chip datasets (GSE33113, GSE23878 and GSE41328) to identify 105 differentially expressed genes (DEGs) that were common to the three datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the highest proportion of up-regulated DEGs was involved in extracellular region and cytokine-cytokine receptor interaction pathways. Integral components of membrane and bile secretion pathways were identified as containing down-regulated DEGs. 13 hub DEGs were chosen and their expression were further validated by GEPIA. Only four DEGs (ADH1C, CLCA4, CXCL8 and GUCA2A) were associated with a significantly lower overall survival after the prognosis analysis. Lower ADH1C protein level and higher CXCL8 protein level were verified by immunohistochemical staining and western blot in clinical CRC and normal colorectal tissues. In conclusion, our study indicated that the extracellular tumor microenvironment and bile metabolism pathways play critical roles in the formation and progression of CRC. Furthermore, we confirmed ADH1C being down-regulated in CRC and reported ADH1C as a prognostic predictor for the first time.