Aluminum exposure promotes the metastatic proclivity of human colorectal cancer cells through matrix metalloproteinases and the TGF-β/Smad signaling pathway

Abstract

Human exposure to aluminum (Al) mainly occurs through food intake. However, influences of Al on the gastrointestinal tract have been rarely reported. In particular, the effect of Al on the metastasis and angiogenesis of colorectal cancer cells has not been studied. Thus, we investigated the effect of Al on the metastatic proclivity using the human colorectal cancer cell line, HT-29. Cells were exposed to 1-16 mM AlCl₃ for 3-72 h. The effects of AlCl₃ on HT-29 cells for migration/invasion/adhesion, and metastasis-associated protein and gene expression were evaluated. AlCl₃ promoted cell migration and invasion, whereas it suppressed cell adhesion. AlCl₃-exposed cells showed decreased E-cadherin and increased vimentin and Snail. AlCl₃ increased transforming growth factor-beta (TGF-β) mRNA expression and Smad2/3 nuclear translocation. AlCl₃-treated cells had a higher mRNA expression of matrix metalloproteinase (MMP)-7 and -9 than the control. Particularly, AlCl₃-treated HT-29 cells promoted the angiogenesis of endothelial cells via increasing the secretion of vascular endothelial growth factor. Taken together, AlCl₃ can promote the metastatic proclivity of colorectal cancer cells through MMP-7, -9, and TGF-β/Smad2/3 pathway. Our data suggest that Al exposure of the gastrointestinal tract may be a risk factor for metastasis initiation in colorectal cancer cells.

Keywords: Aluminum; Angiogenesis; Human colorectal cancer cells; Matrix metalloproteinases; Metastasis; TGF-β/Smad.