UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Publication Date

2017-05-30

Document Type

Article

Disciplines

Cancer Biology | Neoplasms | Oncology

Abstract

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.

Keywords

PanIN, invasion, mir-17~92, pancreatic cancer, regression

Rights and Permissions

Copyright : © 2017 Quattrochi et al.

DOI of Published Version

10.18632/oncotarget.16277

Source

Oncotarget. 2017 May 30;8(22):35902-35918. doi: 10.18632/oncotarget.16277. Link to article on publisher's site

Journal/Book/Conference Title

Oncotarget

Related Resources

Link to Article in PubMed

PubMed ID

28415794

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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