MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells

Wei Lun Hwang, Jeng Kae Jiang, Shung Haur Yang, Tse Shun Huang, Hsin Yi Lan, Hao Wei Teng, Chih Yung Yang, Ya Ping Tsai, Chi Hung Lin, Hsei Wei Wang, Muh Hwa Yang

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126 Citations (Scopus)

Abstract

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 Snail HighNumbLow profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.

Original languageEnglish
Pages (from-to)268-280
Number of pages13
JournalNature cell biology.
Volume16
Issue number3
DOIs
Publication statusPublished - 2014
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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    Hwang, W. L., Jiang, J. K., Yang, S. H., Huang, T. S., Lan, H. Y., Teng, H. W., Yang, C. Y., Tsai, Y. P., Lin, C. H., Wang, H. W., & Yang, M. H. (2014). MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells. Nature cell biology., 16(3), 268-280. https://doi.org/10.1038/ncb2910