SNAIL regulates interleukin-8 expression, stem celllike activity, and tumorigenicity of human colorectal carcinoma cells

Background & Aims: Some cancer cells have activities that are similar to those of stem cells from normal tissues, and cell dedifferentiation correlates with poor prognosis. Little is known about the mechanisms that regulate the stem celllike features of cancer cells; we investigated genes associated with stem celllike features of colorectal cancer (CRC) cells. Methods: We isolated colonospheres from primary CRC tissues and cell lines and characterized their gene expression patterns by microarray analysis. We also investigated the biological features of the colonosphere cells. Results: Expanded CRC colonospheres contained cells that expressed high levels of CD44 and CD166, which are markers of colon cancer stem cells, and had many features of cancer stem cells, including chemoresistance and radioresistance, the ability to initiate tumor formation, and activation of epithelial-mesenchymal transition (EMT). SNAIL, an activator of EMT, was expressed at high levels by CRC colonospheres. Overexpression of Snail in CRC cells induced most properties of colonospheres, including cell dedifferentiation. Two hundred twenty-seven SNAIL-activated genes were up-regulated in colonospheres; gene regulatory networks centered around interleukin (IL)-8 and JUN. Blocking IL-8 expression or activity disrupted SNAIL-induced stem celllike features of colonospheres. We observed that SNAIL activated the expression of IL8 by direct binding to its E3/E4 E-boxes. In CRC tissues, SNAIL and IL-8 were coexpressed with the stem cell marker CD44 but not with CD133 or CD24. Conclusions: In human CRC tissues, SNAIL regulates expression of IL-8 and other genes to induce cancer stem cell activities. Strategies that disrupt this pathway might be developed to block tumor formation by cancer stem cells.