MicroRNA-146a Directs the Symmetric Division of Snail-dominant Colorectal Cancer Stem Cells

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2014 Feb 25

PMID 24561623

Citations 162

Authors

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

Affiliations

Soon will be listed here.

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(High)Numb(Low) profile is correlated with cetuximab resistance and a poorer prognosis. This study elucidates a unique mechanism of EMT-induced CRCSC expansion.

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