The Association Of Gli1and β-catenin Promotes Proliferation Of Colon Cancer Cell Via Upregulated C-myc

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in our country. Its progress involves in multi-gene, multi-stage, and multi-factor abnormal accumulation processes. Previous studies demonstrate that both Wnt and Hedgehog signaling pathways play key roles in the embryonic and stem cell development. Their crosstalk deals with the processes of colon cancer recurrence and invasion. However, the mechanisms of the two signaling pathways inter-act are not well understood.In the current study, we assesse the activation of Hedgehog signaling in four colon cancer cell lines by RT-PCR and Western blot, in which Wnt signaling is constitutively activated. Interaction between endogenous Glil and endogenous (3-catenin is examined using immunoprecipitation method. siRNA, LiCl and GANT61are used to analyze the specific regulation mechanism of Glil and β-catenin. Here, we show a novel interaction, by that Glil, a central molecule of the Hedgehog signaling pathway, is associated with β-catenin, the key molecule of Wnt signaling pathway. The expression of Glil and β-catenin is rising congruously in colon cancer cells. The expression level of Glil is elevated as the Wnt signaling activated with LiCl treatment, and decreased by treatment with β-catenin siRNA. Consistently, Over-expression of Glil enhances intracellular P-catenin level. Moreover, β-catenin expression is down-regulated following siRNA Glil and GANT61treatment. Importantly, the association of Glil and β-catenin increases the nucleus input of themselves and results in the up-regulation of C-myc, which in turn promotes cell proliferation and colon cancer transformation. Collectively, these studies suggest that Glil and β-catenin display the crosstalk regulation between Hedgehog and Wnt signaling, by which Hedgehog signaling stimulates the transcriptional output of Wnt pathway causing an elevation of C-myc expression. The inter-act between Hedgehog and Wnt signaling thereby provides a cellular network mechanism and therapeutic targets for colorectal cancer treatment.