title: miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer.
abstract: Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs to regulate endogenous TGFβ1 levels via miR-663/4787-mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). Although DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contributes to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRNAs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT-suppressing role of miR-202 in pancreatic cancer.Implications:These findings support the possibility of combining small molecule-based (e.g., DZNep analogs) or large molecule-based (e.g., miRNAs) epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the antimetastatic potential of current pancreatic cancer therapy.Mol Cancer Res; 15(8); 1029-39. ©2017 AACR.
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio.|Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
authors.forename: Hardik R
authors.initials: HR
authors.lastname: Mody
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Hung
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Pathak
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.
authors.forename: Jazmine
authors.initials: J
authors.lastname: Griffin
authors.affiliation: The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.|Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University, Columbus, Ohio.
authors.forename: Zobeida
authors.initials: Z
authors.lastname: Cruz-Monserrate
authors.affiliation: Division of Pharmaceutics and Pharmaceutical Chemistry, The Ohio State University, Columbus, Ohio. govindarajan.21@osu.edu.|Department of Pharmaceutical and Biomedical Sciences, The University of Georgia, Athens, Georgia.|The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
authors.forename: Rajgopal
authors.initials: R
authors.lastname: Govindarajan
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D000069287:Capecitabine / Q000008:administration & dosage; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D044127:Epigenesis, Genetic / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C569392:MIRN202 microRNA, human; D035683:MicroRNAs; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D003841:Deoxycytidine; C048460:3-deazaneplanocin; D000069287:Capecitabine; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D000241:Adenosine; D000093542:Gemcitabine