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.
Highlights
The rat sarcoma (RAS) genes (KRAS, HRAS, NRAS, and MRAS) represent a family of small GTPases that are activated indirectly via external stimuli, such as ligand-dependent activation of receptor tyrosine kinases.[1,2] KRAS (Kirsten-rat sarcoma viral oncogene homolog) was the first RAS family protein identified
Increased KRAS Levels Are Associated with Poor Clinical Outcomes in Patients with pancreatic ductal adenocarcinoma (PDAC) and triple-negative breast cancer (TNBC) To explore the clinical significance of KRAS expression, we analyzed a subset of patients with PDAC and basal-like breast cancer (BLBC) from The Cancer Genome Atlas (TCGA) by the Kaplan-Meier method, and we used the PROGgeneV2 tool[26] incorporating survival data associated with KRAS in patients with TNBC
Its expression was markedly high in BLBC tissues (n = 14) with respect to normal breast tissues (n = 14) (p = 0.00012), according to TCGA database (Figure S1C). qRT-PCR analysis showed that the KRAS gene was significantly upregulated in most PDAC and TNBC cells (p < 0.05; Figures 1C and 1D)
Summary
The rat sarcoma (RAS) genes (KRAS, HRAS, NRAS, and MRAS) represent a family of small GTPases that are activated indirectly via external stimuli, such as ligand-dependent activation of receptor tyrosine kinases.[1,2] KRAS (Kirsten-rat sarcoma viral oncogene homolog) was the first RAS family protein identified. It primarily functions as a critical on/off switch in cell-signaling networks that connects upstream extracellular signals to downstream pathways to the nucleus.[3] Signals emanating from RAS proteins are relayed through proto-oncogene serine/threonine-protein kinase (RAF), mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase (ERK)1/2 ( known as MAPK1/3) to the nucleus, where downstream transcription factors, including ETS-1, ETS-2, ELK-1, FOS, and MYC, drive transcriptional programs of cell proliferation and survival, including migration, invasion, cytoskeletal changes, and the cell cycle.[4,5,6]. Canonical mutations in the KRAS pathway are uncommon ($5%–12%),[11,12] overexpression of KRAS13 and transcriptional signatures of activation of the KRAS/MAPK pathway are frequently observed in breast cancer cells,[14] often accompanied by epidermal growth factor receptor (EGFR) mutations or amplifications.[15,16] Mounting evidence suggests that the KRAS/MAPK pathway is highly prevalent and constitutes a major component of oncogenic activity in triple-negative breast cancer (TNBC), more so than in other subtypes of breast cancer.[14,17,18,19] Owing to the failure of farnesyltransferase inhibitors in clinical trials and the lack of small molecule therapeutics approved for directly targeting KRAS,[20] current strategies involve targeting downstream components in the pathway, such as mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors.[5]
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