Dey, ShatovishaKwon, Jason J.Liu, ShengHodge, Gabriel A.Taleb, SolaemaZimmers, Teresa A.Wan, JunKota, Janaiah2021-04-132021-04-132020-02-01Dey, S., Kwon, J. J., Liu, S., Hodge, G. A., Taleb, S., Zimmers, T. A., Wan, J., & Kota, J. (2020). MiR-29a Is Repressed by MYC in Pancreatic Cancer and Its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2. Molecular Cancer Research, 18(2), 311–323. https://doi.org/10.1158/1541-7786.MCR-19-05941541-7786, 1557-3125https://hdl.handle.net/1805/25626Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer with a dismal prognosis. MicroRNA-29a (miR-29a) is commonly downregulated in PDAC, 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-seq 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’-UTR 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 anti-tumorigenic, 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. Implications This study unravels a novel functional role of miR-29a in PDAC pathogenesis, and identifies a MYC-miR-29a-LOXL2 axis in regulation of the disease progression, implicating miR-29a as a potential therapeutic target for PDAC.en-USmicroRNAmiR-29apancreatic cancerRNA-seqLOXL2Article