Department of Molecular, Cell and Cancer Biology
Cancer Biology | Neoplasms | Oncology
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by resistance to currently employed chemotherapeutic approaches. Members of the mir-17~92 cluster of microRNAs (miRNAs) are upregulated in PDAC, but the precise roles of these miRNAs in PDAC are unknown. Using genetically engineered mouse models, we show that loss of mir-17~92 reduces ERK pathway activation downstream of mutant KRAS and promotes the regression of KRASG12D-driven precursor pancreatic intraepithelial neoplasias (PanINs) and their replacement by normal exocrine tissue. In a PDAC model driven by concomitant KRASG12D expression and Trp53 heterozygosity, mir-17~92 deficiency extended the survival of mice that lacked distant metastasis. Moreover, mir-17~92-deficient PDAC cell lines display reduced invasion activity in transwell assays, form fewer invadopodia rosettes than mir-17~92-competent cell lines and are less able to degrade extracellular matrix. Specific inhibition of miR-19 family miRNAs with antagomirs recapitulates these phenotypes, suggesting that miR-19 family miRNAs are important mediators of PDAC cell invasion. Together these data demonstrate an oncogenic role for mir-17~92 at multiple stages of pancreatic tumorigenesis and progression; specifically, they link this miRNA cluster to ERK pathway activation and precursor lesion maintenance in vivo and identify a novel role for miR-19 family miRNAs in promoting cancer cell invasion.
PanIN, invasion, mir-17~92, pancreatic cancer, regression
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Copyright : © 2017 Quattrochi et al.
DOI of Published Version
Oncotarget. 2017 May 30;8(22):35902-35918. doi: 10.18632/oncotarget.16277. Link to article on publisher's site
Quattrochi BJ, Gulvady A, Driscoll DR, Sano M, Klimstra DS, Turner CE, Lewis BC. (2017). MicroRNAs of the mir-17~92 cluster regulate multiple aspects of pancreatic tumor development and progression. Open Access Articles. https://doi.org/10.18632/oncotarget.16277. Retrieved from https://escholarship.umassmed.edu/oapubs/3151
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