title: MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2).
abstract: The overexpression of microRNA-21 (miR-21) is linked to a number of human tumors including colorectal cancer, where it appears to regulate the expression of tumor suppressor genes including p21, phosphatase and tensin homolog, TGFβ receptor II, and B-cell leukemia/lymphoma 2 -associated X protein. Here we demonstrate that miR-21 targets and down-regulates the core mismatch repair (MMR) recognition protein complex, human mutS homolog 2 (hMSH2) and 6 (hMSH6). Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU)-induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component. Moreover, xenograft studies demonstrate that miR-21 overexpression dramatically reduces the therapeutic efficacy of 5-FU. These studies suggest that the down-regulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer.
authors.affiliation: Departments of Molecular Virology, Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Valeri
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gasparini
authors.forename: Chiara
authors.initials: C
authors.lastname: Braconi
authors.forename: Alessio
authors.initials: A
authors.lastname: Paone
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Muller
authors.initials: M
authors.lastname: Fabbri
authors.forename: Khlea M
authors.initials: KM
authors.lastname: Sumani
authors.forename: Hansjuerg
authors.initials: H
authors.lastname: Alder
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.forename: Tushar
authors.initials: T
authors.lastname: Patel
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Nuovo
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
mesh_terms: D020137:Base Pair Mismatch; D015179:Colorectal Neoplasms / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics*; D004351:Drug Resistance / Q000235:genetics*; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D051718:MutS Homolog 2 Protein / Q000235:genetics*
chemical_list: C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D051718:MutS Homolog 2 Protein; D005472:Fluorouracil