Deregulated microRNAs (miRNAs) have been reported to be of functional relevance for tumor biology. In this study, we analyzed the small RNA transcriptomes of 10 paired colorectal cancer samples using SOLiD next-generation sequencing, and generated a total of >15141000 reads. miRNA expression profiles obtained by SOLiD sequencing correlated well with quantitative PCR results. The results showed that the expression of 36 miRNAs was significantly different between the two groups of samples. Additionally, we explored the global miRNA-mRNA interactions using a statistical model. In-depth analysis reveals a diagram of extensive post-transcriptional miRNA regulations. Signaling pathways associated with the miRNA altered expression signature were identified using gene enrichment analysis. The results suggest that these microRNAs, in the aggregate, regulate signaling pathways, such as MAPK, Wnt and p53 pathways in cancer, which are known to be involved in the transformation of colorectal cancer. This evidence demonstrates that miRNAs can cooperatively regulate a given pathway and play a subtle role by regulating their target genes.