The E2A gene, which encodes two basic helix–loop–helix transcription factors, E12 and E47, regulates colorectal cancer progression and epithelial-mesenchymal transition. However, whether E2A regulates the tumor-initiating capacity of colorectal cancer is unclear. Thus, we have studied E2A expression in the initiation of colorectal cancer in vivo and in vitro.

Immunohistochemistry and immunoblot were performed to determine protein levels of E2A in colorectal cancer specimens and cells. RNAi was employed to downregulate E2A expression, and the subsequent change in protein level was evaluated by immunoblot. Sphere-forming assay and enumeration of liver metastasis in mouse models were used to identify the tumor formation ability of colorectal cancer cells.

E2A expression in colorectal cancer clinical specimens was inversely associated with patients’ progression-free survival. Functional studies demonstrated that E2A significantly decreased tumor formation in vitro and in vivo. Furthermore, nuclear translocation of beta-catenin and activation of the Wnt/beta-catenin pathway occurred after suppression of E2A in colorectal cancer cells. FoxM1 was identified as a down-stream target by mRNA microarray, implying that FoxM1 plays a main role in determining how E2A regulates the tumor-initiating capacity of colorectal cancer.

E2A suppresses tumor-initiating capacity by targeting the FoxM1-Wnt/β-catenin pathway.