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Browsing by Subject "miR-29a"
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Item Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment(BMC, 2020-07-13) Dey, Shatovisha; Liu, Sheng; Factora, Tricia D.; Taleb, Solaema; Riverahernandez, Primavera; Udari, Lata; Zhong, Xiaoling; Wan, Jun; Kota, Janaiah; Medical and Molecular Genetics, School of MedicineBackground Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancies with a nearly equal incidence and mortality rates in patients. Pancreatic stellate cells (PSCs) are critical players in PDAC microenvironment to promote the aggressiveness and pathogenesis of the disease. Dysregulation of microRNAs (miRNAs) have been shown to play a significant role in progression of PDAC. Earlier, we observed a PSC-specific downregulation of miR-29a in PDAC pancreas, however, the mechanism of action of the molecule in PSCs is still to be elucidated. The current study aims to clarify the regulation of miR-29a in PSCs and identifies functionally important downstream targets that contribute to tumorigenic activities during PDAC progression. Methods In this study, using RNAseq approach, we performed transcriptome analysis of paired miR-29a overexpressing and control human PSCs (hPSCs). Enrichment analysis was performed with the identified differentially expressed genes (DEGs). miR-29a targets in the dataset were identified, which were utilized to create network interactions. Western blots were performed with the top miR-29a candidate targets in hPSCs transfected with miR-29a mimic or scramble control. Results RNAseq analysis identified 202 differentially expressed genes, which included 19 downregulated direct miR-29a targets. Translational repression of eight key pro-tumorigenic and -fibrotic targets namely IGF-1, COL5A3, CLDN1, E2F7, MYBL2, ITGA6 and ADAMTS2 by miR-29a was observed in PSCs. Using pathway analysis, we find that miR-29a modulates effectors of IGF-1-p53 signaling in PSCs that may hinder carcinogenesis. We further observe a regulatory role of the molecule in pathways associated with PDAC ECM remodeling and tumor-stromal crosstalk, such as INS/IGF-1, RAS/MAPK, laminin interactions and collagen biosynthesis. Conclusions Together, our study presents a comprehensive understanding of miR-29a regulation of PSCs, and identifies essential pathways associated with PSC-mediated PDAC pathogenesis. The findings suggest an anti-tumorigenic role of miR-29a in the context of PSC-cancer cell crosstalk and advocates for the potential of the molecule in PDAC targeted therapies.Item miR-29a Is Repressed by MYC in Pancreatic Cancer and Its Restoration Drives Tumor-Suppressive Effects via Downregulation of LOXL2(American Association for Cancer Research, 2020-02-01) Dey, Shatovisha; Kwon, Jason J.; Liu, Sheng; Hodge, Gabriel A.; Taleb, Solaema; Zimmers, Teresa A.; Wan, Jun; Kota, Janaiah; Medical and Molecular Genetics, School of MedicinePancreatic 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.