Microcystin-LR promotes migration and invasion of colorectal cancer through matrix metalloproteinase-13 up-regulation

Abstract

Microcystin-LR (MC-LR) is an environmental toxin from blooms of cyanobacteria and it has been shown to be one of the environmental carcinogens for the progression of colorectal carcinoma. However, there is no direct evidence that MC-LR can induce colorectal cancer migration and invasion. In the present study, 0.04 or 40 µg/kg/d (human tolerable daily intake value of MC-LR) MC-LR treatment was observed to induce Matrix Metalloproteinase-13 (MMP-13) expression in tumor tissues and local invasion in DLD-1 xenograft model. The results are consistent with those of cell test showing that MC-LR treatment enhanced migration and invasion of DLD-1, HT-29, and SW480 cells and are also correlated with the increased mRNA and protein levels of MMP-13 by Quantitative real-time PCR, Luciferase assay, and Western blot assay respectively in DLD-1 cells and HT-29 cells after MC-LR exposure. In addition, MMP-13 siRNA inhibited MC-LR induced migration and invasion enhancement and MMP-13 over-expression in DLD-1 cells and HT-29 cells. This is the first paper confirming MC-LR-induced MMP-13 expression can promote colorectal cancer invasion and migration. Further investigation revealed that phosphorylation of AKT increased in MC-LR-treated cells, and the phosphatidylinositol 3-kinase/Akt. (PI3-K/AKT) inhibitor LY294002 effectively abolished MC-LR-enhanced migration and invasion and MMP-13 expression. Therefore, based on these observations, we concluded that the activation of PI3K/AKT by MC-LR results in MMP-13 expression, leading to the migration and invasion of DLD-1 cells and HT-29 cells. The study provides a mechanistic insight into the promoting colorectal cancer functions of MC-LR.

Keywords: CRC; Invasion/migration; MC-LR; MMP-13; PI3-K/AKT.