Inhibition of miR-21 Regulates Mutant KRAS Effector Pathways and Intercepts Pancreatic Ductal Adenocarcinoma Development
| Autor: | Aleksandra Popovic, Nina Chu, Minwei Cao, Alexander Hopkins, Elana J. Fertig, Todd D. Armstrong, Robert A. Anders, Bridget P. Keenan, Jacquelyn W. Zimmerman, Elizabeth M. Jaffee |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Apoptosis Biology medicine.disease_cause Article Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Mice 0302 clinical medicine Stroma microRNA medicine Biomarkers Tumor Tumor Cells Cultured Animals Humans Epigenetics Cell Proliferation Effector Prognosis Phenotype Epithelium Gene Expression Regulation Neoplastic Mice Inbred C57BL Pancreatic Neoplasms MicroRNAs 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Mutation Cancer research KRAS Carcinogenesis Carcinoma Pancreatic Ductal |
| Zdroj: | Cancer Prev Res (Phila) |
| ISSN: | 1940-6215 |
| Popis: | Almost all pancreatic ductal adenocarcinomas (PDA) develop following KRAS activation, which triggers epithelial transformation and recruitment of desmoplastic stroma through additional transcriptional and epigenetic regulation, but only a few of these regulatory mechanisms have been described. We profiled dysregulated miRNAs starting with the earliest premalignant pancreatic intraepithelial neoplasias (PanIN) in genetically engineered mutated KRAS and P53 (KPC) mice programmed to recapitulate human PDA tumorigenesis. We identified miR-21 and miR-224 as cell-specific and compartment-specific regulators in PanINs and PDA. miR-21 is overexpressed in tumor epithelial cells of premalignant ducts, while miR-224 is overexpressed in cancer-associated fibroblasts in PDA stroma. Inhibition of miR-21 reverted protumorigenic functionalities to baseline levels. Overexpression of miR-224 induced activated phenotypes in normal fibroblasts. In vivo miR-21 inhibition improved survival in established PDA. Importantly, early systemic miR-21 inhibition completely intercepted premalignant progression. Finally, an evaluation of miR-21 expression in the PDA cohort of The Cancer Genome Atlas identified a correlation between tumor epithelial cell content and miR-21 expression in human tumors providing further rationale for conducting human studies. Thus, miR-21 may be useful for early PanIN detection, and for intercepting developing premalignant pancreatic lesions and other KRAS-driven premalignancies. |
| Databáze: | OpenAIRE |
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