Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment

dc.contributor.authorDey, Shatovisha
dc.contributor.authorLiu, Sheng
dc.contributor.authorFactora, Tricia D.
dc.contributor.authorTaleb, Solaema
dc.contributor.authorRiverahernandez, Primavera
dc.contributor.authorUdari, Lata
dc.contributor.authorZhong, Xiaoling
dc.contributor.authorWan, Jun
dc.contributor.authorKota, Janaiah
dc.contributor.departmentMedical and Molecular Genetics, School of Medicineen_US
dc.date.accessioned2021-01-28T19:15:40Z
dc.date.available2021-01-28T19:15:40Z
dc.date.issued2020-07-13
dc.description.abstractBackground 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.en_US
dc.identifier.citationDey, S., Liu, S., Factora, T. D., Taleb, S., Riverahernandez, P., Udari, L., Zhong, X., Wan, J., & Kota, J. (2020). Global targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironment. BMC Cancer, 20(1), 651. https://doi.org/10.1186/s12885-020-07135-2en_US
dc.identifier.issn1471-2407en_US
dc.identifier.urihttps://hdl.handle.net/1805/25039
dc.language.isoen_USen_US
dc.publisherBMCen_US
dc.relation.isversionof10.1186/s12885-020-07135-2en_US
dc.relation.journalBMC Canceren_US
dc.rightsAttribution 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.sourcePMCen_US
dc.subjectPancreatic canceren_US
dc.subjectPDACen_US
dc.subjectPSCsen_US
dc.subjectmicroRNAen_US
dc.subjectmiR-29aen_US
dc.subjectProtein interaction networken_US
dc.subjectRNAseqen_US
dc.subjectDesmoplasiaen_US
dc.subjectTumor microenvironmenten_US
dc.subjectECMen_US
dc.titleGlobal targetome analysis reveals critical role of miR-29a in pancreatic stellate cell mediated regulation of PDAC tumor microenvironmenten_US
dc.typeArticleen_US
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