The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers

Hamada A. Mokhlis, Recep Bayraktar, Nashwa N. Kabil, Ayse Caner, Nermin Kahraman, Cristian Rodriguez-Aguayo, Erika P. Zambalde, Jianting Sheng, Kübra Karagoz, Pinar Kanlikilicer, Abdel Aziz H. Abdel Aziz, Tamer M. Abdelghany, Ahmed A. Ashour, Stephen Wong, Michael L. Gatza, George A. Calin, Gabriel Lopez-Berestein, Bulent Ozpolat

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3′ UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

Original languageEnglish (US)
Pages (from-to)301-317
Number of pages17
JournalMolecular Therapy - Nucleic Acids
Volume14
Early online dateDec 13 2018
DOIs
StatePublished - Mar 1 2019

Keywords

  • KRAS
  • breast cancer
  • gene regulation
  • gene silencing
  • invasion
  • liposomes
  • miR-873
  • microRNA
  • nanoparticles
  • ncRNA
  • non-coding RNA
  • oncogene
  • pancreatic cancer
  • proliferation
  • therapy
  • triple-negative breast cancer
  • tumorigenesis

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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