MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells
Menée in vitro, in vivo et sur des échantillons tumoraux prélevés sur des patients atteints d'un cancer colorectal, cette étude met en évidence des mécanismes par lesquels le micro-ARN miR-146a régule la division symétrique des cellules souches de cancer colorectal et, ainsi, la transition épithélio-mésenchymateuse
Asymmetrical cell division (ACD) maintains the proper number of stem cells to ensure self-renewal. In cancer cells, the deregulation of ACD disrupts the homeostasis of the stem cell pool and promotes tumour growth. However, this mechanism is unclear. Here, we show a reduction of ACD in spheroid-derived colorectal cancer stem cells (CRCSCs) compared with differentiated cancer cells. The epithelial–mesenchymal transition (EMT) inducer Snail is responsible for the ACD-to-symmetrical cell division (SCD) switch in CRCSCs. Mechanistically, Snail induces the expression of microRNA-146a (miR-146a) through the β-catenin–TCF4 complex. miR-146a targets Numb to stabilize β-catenin, which forms a feedback circuit to maintain Wnt activity and directs SCD. Interference with the Snail–miR-146a–β-catenin loop by inhibiting the MEK or Wnt activity reduces the symmetrical division of CRCSCs and attenuates tumorigenicity. In colorectal cancer patients, the SnailHighNumbLow profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.