DKK4 is important in Snail1-induced chemoresistance to fluorouracilin colorectal cancer

Wenbin Shen, Long Cui, Wei Chen


Background: The overexpression of Snail1 is correlated with the epithelial-mesenchymal transition (EMT) in many cancers. However, the correlation between Snail1 and chemoresistance in colorectal cancer (CRC) as well as the underlying mechanism remain unknown. In this study, we evaluated the relationship between Snail1 and chemoresistance in CRC and determined whether DKK4 was involved in Snail1-induced chemoresistance.
Methods: IHC was performed to determine the correlation between Snail1 and DKK4 and their relationship to chemoresistance in CRC. Additionally, a cellular functional assay was performed to study the DKK4 expression regulated by Snail1 in CRC cell lines.
Results: In our cohort, a high level of Snail1 indicated chemoresistance and poor prognosis. Furthermore, a strong correlation between DKK4 and Snail1 was observed in our CRC samples. Knockdown of Snail1 in LoVo cells resulted in the downregulation of DKK4, whereas the overexpression of Snail1 in CRC cell lines resulted in resistance to 5-fluorourcil (5 FU) treatment, with an up-regulation of the DKK4 level. Knockdown of DKK4 by siRNA in Snail1-overexpressing CRC cell lines reversed the resistance to 5 FU treatment induced by Snail1 overexpression.
Conclusions: Taken together, our results indicated that DKK4 could be a downstream gene that is regulated by Snail1 and could play an important role in Snail1-induced CRC chemoresistance to 5 FU. Targeting downstream Snail1 genes may provide a new therapeutic strategy for the treatment of advanced CRC.