期刊
MOLECULAR CANCER RESEARCH
卷 18, 期 2, 页码 311-323出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-19-0594
关键词
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资金
- American Cancer Society [RSG18-105-01-RMC]
- NIH/NCRR Grant from the Indiana CTSI [UL1TR001108]
- NCI [1 F31 CA213731-01A1]
- IU Simon Cancer Center [P30CA082709]
- Purdue University Center for Cancer Research [P30CA023168]
- Walther Cancer Foundation
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer with a dismal prognosis. miR-29a is commonly downregulated inPDAC; however, mechanisms for its loss and role still remain unclear. Here, we show that in PDAC, repression of miR-29a is directly mediated by MYC via promoter activity. RNA sequencing analysis, integrated with miRNA target prediction, identified global miR-29a downstream targets in PDAC. Target enrichment coupled with gene ontology and survival correlation analyses identified the top five miR-29a-downregulated target genes (LOXL2, MYBL2, CLDN1, HGK, and NRAS) that are known to promote tumorigenic mechanisms. Functional validation confirmed that upregulation of miR-29a is sufficient to ablate translational expression of these five genes in PDAC. We show that the most promising target among the identified genes, LOXL2, is repressed by miR-29a via 3'-untranslated region binding. Pancreatic tissues from a PDAC murine model and patient biopsies showed overall high LOXL2 expression with inverse correlations with miR-29a levels. Collectively, our data delineate an antitumorigenic, regulatory role of miR-29a and a novel MYC-miR-29a-LOXL2 regulatory axis in PDAC pathogenesis, indicating the potential of the molecule in therapeutic opportunities. [GRAPHICS]
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