Regulation of hnRNPA1 by microRNAs controls the miR-18a–K-RAS axis in chemotherapy-resistant ovarian cancer

Cristian Rodriguez-Aguayo, Paloma del C. Monroig, Roxana S. Redis, Emine Bayraktar, Maria Inês Almeida, Cristina Ivan, Enrique Fuentes-Mattei, Mohammed H. Rashed, Arturo Chavez-Reyes, Bulent Ozpolat, Rahul Mitra, Anil K. Sood, George A. Calin, Gabriel Lopez-Berestein

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

The regulation of microRNA (miRNA) biogenesis, function and degradation involves a range of mechanisms, including interactions with RNA-binding proteins. The potential contribution of regulatory miRNAs to the expression of these RNA interactor proteins that could control other miRNAs expression is still unclear. Here we demonstrate a regulatory circuit involving oncogenic and tumor-suppressor miRNAs and an RNA-binding protein in a chemotherapy-resistant ovarian cancer model. We identified and characterized miR-15a-5p and miR-25-3p as negative regulators of hnRNPA1 expression, which is required for the processing of miR-18a-3p, an inhibitor of the K-RAS oncogene. The inhibition of miR-25-3p and miR-15a-5p decreased the proliferation, motility, invasiveness and angiogenic potential and increased apoptosis when combined with docetaxel. Alteration of this regulatory circuit causes poor overall survival outcome in ovarian cancer patients. These results highlight miR-15a-5p and miR-25-3p as key regulators of miR-18a-3p expression and its downstream target K-RAS, through direct modulation of hnRNPA1 expression. Our results demonstrate the therapeutic potential of inhibiting miR-25-3p and miR-15a-5p and the use of miR-18a-3p/KRAS ratio as a prominent outcome prognostic factor.

Original languageEnglish (US)
Article number17029
JournalCell Discovery
Volume3
DOIs
StatePublished - 2017

Keywords

  • Chemotherapy resistance
  • HnRNPA1
  • K-RAS
  • MicroRNAs
  • Ovarian cancer
  • RNA-binding proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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