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MicroRNAs of the mir-17~92 cluster regulate multiple aspects of pancreatic tumor development and progression
Brian Quattrochi1, Anushree Gulvady2, David R Driscoll1
1Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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.
Insights
The mir-17~92 microRNA cluster promotes pancreatic cancer growth and invasion. Inhibiting this cluster can lead to tumor regression and reduced spread, offering new therapeutic avenues for pancreatic ductal adenocarcinoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with poor treatment outcomes.
- The mir-17~92 microRNA (miRNA) cluster is upregulated in PDAC, but its function is unclear.
Purpose of the Study:
- To investigate the role of the mir-17~92 miRNA cluster in pancreatic cancer development and progression.
- To determine the impact of mir-17~92 on KRAS-driven pancreatic tumorigenesis and invasion.
Main Methods:
- Utilized genetically engineered mouse models of pancreatic cancer.
- Assessed the effects of mir-17~92 deletion on tumor growth, precursor lesion regression, and metastasis.
- Examined PDAC cell invasion, extracellular matrix degradation, and invadopodia formation.
- Investigated the role of miR-19 family miRNAs using antagomirs.
Main Results:
- Loss of mir-17~92 reduced ERK pathway activation downstream of mutant KRAS.
- Mir-17~92 deficiency promoted regression of precursor lesions (PanINs) and extended survival in metastatic PDAC models.
- Mir-17~92-deficient PDAC cells showed decreased invasion, reduced invadopodia formation, and less extracellular matrix degradation.
- Inhibition of miR-19 family miRNAs mimicked these anti-invasive effects.
Conclusions:
- The mir-17~92 cluster plays an oncogenic role throughout pancreatic cancer progression.
- Mir-17~92 is linked to ERK pathway activation and maintenance of precursor lesions in vivo.
- miR-19 family miRNAs are key mediators of PDAC cell invasion, representing potential therapeutic targets.