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 language | English (US) |
---|---|
Pages (from-to) | 301-317 |
Number of pages | 17 |
Journal | Molecular Therapy Nucleic Acids |
Volume | 14 |
DOIs | |
State | Published - 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
MD Anderson CCSG core facilities
- Functional Proteomics Reverse Phase Protein Array Core
- Bioinformatics Shared Resource