Abstract
Chemoresistance is a major obstacle in cancer treatment. Our previous studies have shown that miR-125b plays an important role in chemoresistance. Here we report a novel mechanism that up-regulation of miR-125b through Wnt signaling by Snail enriches cancer stem cells. Overexpression of Snail dramatically increases the expression of miR-125b through the Snail-activated Wnt/β-catenin/TCF4 axis. Snail confers chemoresistance by repressing Bak1 through up-regulation of miR-125b. Restoring the expression of Bak1 or depleting miR-125b re-sensitizes Snail-expressing cancer cells to Taxol, indicating that miR-125b is critical in Snail-induced chemoresistance. Moreover, overexpression of miR-125b significantly increases the cancer stem cell population (CD24-CD44+), while depletion of miR-125b or rescue of the expression of Bak1 increases the non-stem cell population (CD24+CD44+) in Snail-overexpressing cells. These findings strongly support that miR-125b functions as a key mediator in Snail-induced cancer stem cell enrichment and chemoresistance. This novel mechanism for Snail-induced stem cell propagation and chemoresistance may have important implications in the development of strategies for overcoming cancer cell resistance to chemotherapy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Phytogenic / pharmacology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm*
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Humans
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MicroRNAs / biosynthesis*
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MicroRNAs / genetics
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasms / drug therapy
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Neoplasms / genetics
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Neoplasms / metabolism*
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Neoplasms / pathology
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Paclitaxel / pharmacology
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RNA, Neoplasm / biosynthesis*
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RNA, Neoplasm / genetics
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Snail Family Transcription Factors
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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bcl-2 Homologous Antagonist-Killer Protein / genetics
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bcl-2 Homologous Antagonist-Killer Protein / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism
Substances
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Antineoplastic Agents, Phytogenic
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BAK1 protein, human
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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MIRN125 microRNA, human
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MicroRNAs
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Neoplasm Proteins
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RNA, Neoplasm
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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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Wnt Proteins
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bcl-2 Homologous Antagonist-Killer Protein
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beta Catenin
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Paclitaxel