MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2)

Nicola Valeri, Pierluigi Gasparini, Chiara Braconi, Alessio Paone, Francesca Lovat, Muller Fabbri, Khlea M. Sumani, Hansjuerg Alder, Dino Amadori, Tushar Patel, Gerard J. Nuovo, Richard Fishel, Carlo M. Croce

Research output: Contribution to journalArticle

263 Scopus citations

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 downregulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer.

Original languageEnglish (US)
Pages (from-to)21098-21103
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number49
DOIs
StatePublished - Dec 7 2010

Keywords

  • Colon cancer
  • DNA repair
  • Non coding RNA

ASJC Scopus subject areas

  • General

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    Valeri, N., Gasparini, P., Braconi, C., Paone, A., Lovat, F., Fabbri, M., Sumani, K. M., Alder, H., Amadori, D., Patel, T., Nuovo, G. J., Fishel, R., & Croce, C. M. (2010). MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proceedings of the National Academy of Sciences of the United States of America, 107(49), 21098-21103. https://doi.org/10.1073/pnas.1015541107