Microcystin-LR Promotes Migration And Invasion Of Colorectal Cancer Through Matrix Metalloproteinase-13Upregulation

Purpose:Microcystin-LR is an environmental toxin from blooms of cyanobacteria, and it has been shown to be essential for the progression of colorectal carcinoma. However, there is no direct evidence that microcystin-LR can induce colorectal cancer mvasion.Methods:In the present study,0.04μg/kg/day (human tolerable daily intake value of microcystin-LR) microcystin-LR was observed to induce metal matrix proteinase-13(MMP-13) expression in tumor tissues and local invasion in the DLD-1xenograft model. The results are consistent with cell test showing that microcystin-LR treatment (>7.5nM) enhanced migration and invasion of DLD-1cells, which is correlated with an increase in MMP-13expression. Quantitative real-time PCR, Luciferase assay and Western blotting consistently demonstrated that mRNA and protein levels of MMP-13increased in the cells after microcystin-LR exposure. In addition, MMP-13siRNA inhibited microcystin-LR induced migration and invasion enhancement and MMP-13overexpression in DLD-1cells. This is the first paper confirming microcystin-LR-induced MMP-13expression can promote colorectal cancer invasion and migration. Further investigation revealed that phosphorylation of AKT increased in microcystin-LR-treated cells, and the phosphatidylinositol3-kinase/Akt.(PI3-K/AKT) inhibitor LY294002effectively abolished microcystin-LR-triggered migration and invasion enhancement and MMP-13overexpression.Results:Therefore, based on these observations, we concluded that the activation of PI3K/AKT by microcystin-LR results in MMP-13expression, leading to the migration and invasion of DLD-1cells. The study provides a mechanistic insight into the prometastatic functions of microcystin-LR in colorectal cancer.