Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer with a median survival of 6 months with current therapeutic strategies. The majority (~85%) of patients present with locally advanced or metastatic disease, rendering the 5-year survival rate to be only around 1-4%. The mutated K-RAS oncogene is amont the most common oncogenes in human cancer and is present in about 90% of PDAC cases. However, current treatment options targeting KRAS are still very limited, thus warranting the need for development of effective targeted therapeutics in order to improve PDAC patient outcome. miRNAs are a class of small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level. Dysregulation of miRNAs is involved in the pathogenesis of a variety of diseases, including cancer, by regulating cell signaling pathways including apoptosis, cell cycle, migration/invasion, and metastasis. Oncogenic miRNAs have become major targets for novel therapies, while tumor suppressor miRNAs are being developed as therapeutic tools to inhibit expression of oncogenes in various cancers. Thus, inhibition of KRAS using miRNAs represents an appealing strategy to suppress PDAC progression. To identify potential regulators of KRAS we used various predictive algorithms including TargetScan, Diana tools and microRNA.org, and identified miR-873 as a potential regulator of KRAS. We analyzed basal miR-873 expression in PDAC cells and found it to be significantly downregulated compared with normal pancreatic epithelial cells. Using luciferase-gene reporter assay, we demonstrated that miR-873 directly binds to the 3′-UTR of KRAS mRNA and suppresses its expression. In vitro delivery of miR-873 into mutated KRAS-driven PDAC cells (PANC 1 and Mia-Paca-2) inhibited their proliferation, colony formation, migration and invasion. Furthermore, ectopic delivery of miR-873 decreased the expression of KRAS downstream signaling pathways (e.g., Akt, ERK). To target KRAS in PDAC models we recently developed single-lipid based nanoparticles (SLNP) loaded with KRAS siRNA or microRNA, which provide robust and sustained silencing of target genes, including KRAS. We also found that in vivo targeting of mutated KRAS significantly enhances in vivo perfusion of tumors detected by photoacoustic imaging. Remarkably, in vivo intravenous systemic administration of SLNP-MiR-873 nanotherapeutics (0.3mg/kg miR-873) suppressed tumor growth in PDAC xenograft models (PANC 1 and Mia-Paca-2) and silenced mutated KRAS expression. Overall, our results suggest that targeted delivery and restoration of miR-873 may be a potential therapeutic approach against PDAC.
Citation Format: Hamada A. Mokhlis, Recep Bayraktar, Nashwa N. Kabil, Nermin Kahraman, Richard Bouchard, Tamer Abdelghany, Ahmed Ashour, Abdel-Aziz H. Abdel-Aziz, George A. Calin, Gabriel Lopez-Berestein, Bulent Ozpolat. MiR-873 functions as a potential tumor suppressor in pancreatic cancer by targeting KRAS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 507.