期刊
ONCOTARGET
卷 8, 期 22, 页码 35902-35918出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.16277
关键词
pancreatic cancer; mir-17 similar to 92; PanIN; regression; invasion
资金
- American Association for Cancer Research [09-60-25-LEWI]
- Pancreatic Cancer Action Network
- NIH [R01 CA163296, F30CA168063]
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by resistance to currently employed chemotherapeutic approaches. Members of the mir-17 similar to 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 similar to 92 reduces ERK pathway activation downstream of mutant KRAS and promotes the regression of KRAS(G12D)-driven precursor pancreatic intraepithelial neoplasias (PanINs) and their replacement by normal exocrine tissue. In a PDAC model driven by concomitant KRAS(G12D) expression and Trp53 heterozygosity, mir-17 similar to 92 deficiency extended the survival of mice that lacked distant metastasis. Moreover, mir-17 similar to 92-deficient PDAC cell lines display reduced invasion activity in transwell assays, form fewer invadopodia rosettes than mir-17 similar to 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 similar to 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.
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