title: miR-125b functions as a key mediator for snail-induced stem cell propagation and chemoresistance.
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.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Shruti
authors.initials: S
authors.lastname: Desai
authors.forename: David C
authors.initials: DC
authors.lastname: Schmitt
authors.forename: Ming
authors.initials: M
authors.lastname: Zhou
authors.forename: Hung T
authors.initials: HT
authors.lastname: Khong
authors.forename: Kristine S
authors.initials: KS
authors.lastname: Klos
authors.forename: Steven
authors.initials: S
authors.lastname: McClellan
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D000071250:Snail Family Transcription Factors; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C494772:BAK1 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D000071250:Snail Family Transcription Factors; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051153:Wnt Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051176:beta Catenin; D017239:Paclitaxel