Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting ß-catenin nuclear translocation

Epithelial-mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of ss-catenin in this process is elusive. We identified that LIM domain kinase (LIMK) 2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain-and loss-of-function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1-S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of ss-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via ss-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy.