Aberrant regulation of APC/beta-catenin signaling pathway is common in the pathogenesis of colorectal and other cancers. Targets regulated by APC/beta-catenin signaling pathway play crucial roles in cancer development. In the current study, we aimed to illustrate the influence of APC/beta-catenin signaling pathway on expression of microRNAs, one new group of players important to carcinogenesis. Restoration of APC function in colorectal cancer cells led to the deregulation of several cancer-related microRNAs, such as miR-122a which was recognized as the liver-specific microRNA. MiR-122a was down-regulated in gastrointestinal cancer cell lines as well as primary carcinoma tissues. Inhibition of miR-122a could reverse wild-type APC-induced growth inhibition of gastrointestinal cancer cells while miR-122a mimic inhibited cell growth. In summary, we identified some cancer-related microRNAs regulated by APC/beta-catenin signaling pathway. The down-regulation of miR-122a mediated by aberrant APC/beta-catenin signaling is important to the pathogenesis of gastrointestinal cancers.