title: Pathophysiological role of microRNA-29 in pancreatic cancer stroma.
abstract: Dense fibrotic stroma associated with pancreatic ductal adenocarcinoma (PDAC) is a major obstacle for drug delivery to the tumor bed and plays a crucial role in pancreatic cancer progression. Current, anti-stromal therapies have failed to improve tumor response to chemotherapy and patient survival. Furthermore, recent studies show that stroma impedes tumor progression, and its complete ablation accelerates PDAC progression. In an effort to understand the molecular mechanisms associated with tumor-stromal interactions, using in vitro and in vivo models and PDAC patient biopsies, we show that the loss of miR-29 is a common phenomenon of activated pancreatic stellate cells (PSCs)/fibroblasts, the major stromal cells responsible for fibrotic stromal reaction. Loss of miR-29 is correlated with a significant increase in extracellular matrix (ECM) deposition, a major component in PDAC stroma. Our in vitro miR-29 gain/loss-of-function studies document the role of miR-29 in PSC-mediated ECM stromal protein accumulation. Overexpression of miR-29 in activated stellate cells reduced stromal deposition, cancer cell viability, and cancer growth in co-culture. Furthermore, the loss of miR-29 in TGF-β1 activated PSCs is SMAD3 dependent. These results provide insights into the mechanistic role of miR-29 in PDAC stroma and its potential use as a therapeutic agent to target PDAC.
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Kwon
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nabinger
authors.affiliation: Wabash College, Crawfordsville, IN, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Vega
authors.affiliation: 1] Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA [2] Department of Pathology, IUSM, Indianapolis, IN, USA.
authors.forename: Smiti Snigdha
authors.initials: SS
authors.lastname: Sahu
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Alluri
authors.affiliation: Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA.
authors.forename: Zahi
authors.initials: Z
authors.lastname: Abdul-Sater
authors.affiliation: Department of Biostatistics, IUSM, Indianapolis, IN, USA.
authors.forename: Zhangsheng
authors.initials: Z
authors.lastname: Yu
authors.affiliation: 1] Department of Medicine, IUSM, Indianapolis, IN, USA [2] The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA [3] Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Gore
authors.affiliation: 1] Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA [2] Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA [3] Department of Pediatrics, Herman B Wells Center for Pediatric Research, IUSM, Indianapolis, IN, USA [4] Division of Pediatric Hematology-Oncology, Bone Marrow Failure Program, IUSM, Indianapolis, IN, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
authors.affiliation: Department of Pathology, IUSM, Indianapolis, IN, USA.
authors.forename: Romil
authors.initials: R
authors.lastname: Saxena
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, IUSM, Indianapolis, IN, USA [2] Department of Medicine, IUSM, Indianapolis, IN, USA [3] The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA [4] Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
authors.affiliation: 1] Department of Medical and Molecular Genetics, Indiana University School of Medicine (IUSM), Indianapolis, IN, USA [2] The Melvin and Bren Simon Cancer Center, IUSM, Indianapolis, IN, USA [3] Center for Pancreatic Cancer Research, Indiana University and Purdue University-Indianapolis (IUPUI), Indianapolis, IN, USA.
authors.forename: Janaiah
authors.initials: J
authors.lastname: Kota
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D005355:Fibrosis / Q000235:genetics / Q000473:pathology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D058954:Pancreatic Stellate Cells / Q000166:cytology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D016283:Proto-Oncogene Proteins p21(ras)