Relevant to our MMP data, Snail has been shown to directly stimulate MMP-2 and MMP-9 expression(Yokoyama et al., 2003, Jorda et al., 2005). Knockdown of Snail in a mouse tumor model resulted in fewer tumors at least in part due to reduced MMP-9 (Olmeda et al., 2007). MMP-3 or MMP-9 can also further promote EMT via Snail (Radisky et al., 2005). In addition, MMP-7 is a target of β-catenin/TCF signaling which is another pathway important in EMT also tied to Snail (Peinado et al., 2007, Brabletz et al., 1999). Increased Snail activity can stimulate β-catenin indirectly by repressing E-cadherin or directly by interacting with β-catenin (Stemmer et al., 2008). Our data supports a mechanism in which alcohol stimulation of activated Snail nuclear localization as well as increased Snail mRNA expression results in promoting EMT and cancer progression by increasing expression of vimentin as well as MMP-2, MMP-7, and MMP-9 in cancer cells.
