title: MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer.
abstract: Pancreatic cancer has a poor prognosis due to late diagnosis and ineffective therapeutic multimodality. MUC13, a transmembrane mucin is highly involved in pancreatic cancer progression. Thus, understanding its regulatory molecular mechanisms may offer new avenue of therapy for prevention/treatment of pancreatic cancer. Herein, we report a novel microRNA (miR-145)-mediated mechanism regulating aberrant MUC13 expression in pancreatic cancer. We report that miR-145 expression inversely correlates with MUC13 expression in pancreatic cancer cells and human tumor tissues. miR-145 is predominantly present in normal pancreatic tissues and early Pancreatic Ductal Adenocarcinoma (PDAC) precursor lesions (PanIN I) and is progressively suppressed over the course of development from PanIN II/III to late stage poorly differentiated PDAC. We demonstrate that miR-145 targets 3' untranslated region of MUC13 and thus downregulates MUC13 protein expression in cells. Interestingly, transfection of miR-145 inhibits cell proliferation, invasion and enhances gemcitabine sensitivity. It causes reduction of HER2, P-AKT, PAK1 and an increase in p53. Similar results were found when MUC13 was specifically inhibited by shRNA directed at MUC13. Additionally, intratumoral injections of miR-145 in xenograft mice inhibited tumor growth via suppression of MUC13 and its downstream target, HER2. These results suggest miR-145 as a novel regulator of MUC13 in pancreatic cancer.
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Sheema
authors.initials: S
authors.lastname: Khan
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA.
authors.forename: Mara C
authors.initials: MC
authors.lastname: Ebeling
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Mohd S
authors.initials: MS
authors.lastname: Zaman
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Sikander
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Murali M
authors.initials: MM
authors.lastname: Yallapu
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Chauhan
authors.affiliation: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee , USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Yacoubian
authors.affiliation: Department of Surgery, University of Tennessee Health Science Center, Memphis, Tennessee , USA.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Behrman
authors.affiliation: Department of Pathology, University of Tennessee Health Science Center, Memphis, Tennessee , USA.
authors.forename: Nadeem
authors.initials: N
authors.lastname: Zafar
authors.affiliation: Department of Biological and Environmental Sciences, University of the District of Columbia, Washington, District of Columbia.
authors.forename: Deepak
authors.initials: D
authors.lastname: Kumar
authors.affiliation: Cancer Biology Research Center, Sanford Research/USD, Sioux Falls, South Dakota, USA. Methodology and Data Analysis Center, Sanford Research, Sioux Falls, South Dakota, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Thompson
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Meena
authors.initials: M
authors.lastname: Jaggi
authors.affiliation: Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
authors.forename: Subhash C
authors.initials: SC
authors.lastname: Chauhan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C541010:MIRN145 microRNA, human; C429552:MUC13 protein, human; D035683:MicroRNAs; D009077:Mucins