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
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3' Untranslated Regions
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Adenocarcinoma / mortality
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Adenocarcinoma / pathology*
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology
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Antineoplastic Agents / pharmacology
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Base Sequence
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Binding Sites
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Cell Line, Tumor
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Cetuximab
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Colorectal Neoplasms / drug therapy
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / mortality
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Colorectal Neoplasms / pathology*
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Drug Resistance, Neoplasm
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Kaplan-Meier Estimate
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Mitosis*
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Neoplastic Stem Cells / physiology*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Prognosis
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Proteolysis
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Snail Family Transcription Factors
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Transcription Factor 4
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Transcription, Genetic
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Tumor Burden / drug effects
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Wnt Signaling Pathway
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Xenograft Model Antitumor Assays
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beta Catenin / metabolism
Substances
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3' Untranslated Regions
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CTNNB1 protein, human
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MIRN146 microRNA, human
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Membrane Proteins
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MicroRNAs
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Nerve Tissue Proteins
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NUMB protein, human
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Snail Family Transcription Factors
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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beta Catenin
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Cetuximab