MicroRNA-146a directs the symmetric division of Snail-dominant colorectal cancer stem cells.
Nat Cell Biol, 2014/3;16(3):268-80.
Hwang WL, Jiang JK, Yang SH, Huang TS, Lan HY, Teng HW, Yang CY, Tsai YP, Lin CH, Wang HW, Yang MH
PMID: 24561623DOI: 10.1038/ncb2910
Impact factor: 28.213
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.
MeSH terms
3' Untranslated Regions; Adenocarcinoma; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Binding Sites; Cell Line, Tumor; Cetuximab; Colorectal Neoplasms; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Nude; MicroRNAs; Mitosis; Neoplastic Stem Cells; Nerve Tissue Proteins; Prognosis; Proteolysis; Snail Family Transcription Factors; Transcription Factor 4; Transcription Factors; Transcription, Genetic; Tumor Burden; Wnt Signaling Pathway; Xenograft Model Antitumor Assays; beta Catenin
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