Blockage of TGFβ-SMAD2 by demethylation-activated miR-148a is involved in caffeic acid-induced inhibition of cancer stem cell-like properties in vitro and in vivo

Current standard practices for treatment of cancers are less than satisfactory because of recurrence mediated by cancer stem cells (CSCs). Caffeic acid (CaA) is a novel anti-tumor agent that inhibits proliferation, migration, and invasion in human cancer cells. However, little is known about the functions of CaA in regulating CSCs-like properties and the potential molecular mechanisms. Here, we found that CaA attenuated the CSCs-like properties by the microRNA-148a (miR-148a)-mediated inhibition of transforming growth factor beta (TGFβ)-SMAD2 signaling pathway both in vitro and in vivo. CaA enhanced the expression of miR-148a by inducing DNA methylation. MiR-148a, which targeted the SMAD2-3'UTR, decreased the expression of SMAD2. Knockdown of miR-148a abolished the CaA-induced inhibition of TGFβ-SMAD2 signal pathway and the CSCs-like properties. Our study found a novel mechanism that CaA inhibits the CSCs-like properties via miR-148a-mediated inhibition of TGFβ-SMAD2 signaling pathway, which may help to identify a new approach for the treatment of human cancers.