title: DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism.
abstract: Pancreatic cancer is an exceptionally aggressive disease in great need of more effective therapeutic options. Epithelial-mesenchymal transition (EMT) plays a key role in cancer invasion and metastasis, and there is a gain of stem cell properties during EMT. Here we report increased expression of the putative pancreatic stem cell marker DCAMKL-1 in an established KRAS transgenic mouse model of pancreatic cancer and in human pancreatic adenocarcinoma. Colocalization of DCAMKL-1 with vimentin, a marker of mesenchymal lineage, along with 14-3-3 σ was observed within premalignant PanIN lesions that arise in the mouse model. siRNA-mediated knockdown of DCAMKL-1 in human pancreatic cancer cells induced microRNA miR-200a, an EMT inhibitor, along with downregulation of EMT-associated transcription factors ZEB1, ZEB2, Snail, Slug, and Twist. Furthermore, DCAMKL-1 knockdown resulted in downregulation of c-Myc and KRAS through a let-7a microRNA-dependent mechanism, and downregulation of Notch-1 through a miR-144 microRNA-dependent mechanism. These findings illustrate direct regulatory links between DCAMKL-1, microRNAs, and EMT in pancreatic cancer. Moreover, they demonstrate a functional role for DCAMKL-1 in pancreatic cancer. Together, our results rationalize DCAMKL-1 as a therapeutic target for eradicating pancreatic cancers.
authors.affiliation: Department of Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.
authors.forename: Sripathi M
authors.initials: SM
authors.lastname: Sureban
authors.forename: Randal
authors.initials: R
authors.lastname: May
authors.forename: Stan A
authors.initials: SA
authors.lastname: Lightfoot
authors.forename: Aimee B
authors.initials: AB
authors.lastname: Hoskins
authors.forename: Megan
authors.initials: M
authors.lastname: Lerner
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brackett
authors.forename: Russell G
authors.initials: RG
authors.lastname: Postier
authors.forename: Rama
authors.initials: R
authors.lastname: Ramanujam
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.forename: James H
authors.initials: JH
authors.lastname: Wyche
authors.forename: Shrikant
authors.initials: S
authors.lastname: Anant
authors.forename: Courtney W
authors.initials: CW
authors.lastname: Houchen
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D000089742:Doublecortin-Like Kinases; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005092:Exonucleases / Q000378:metabolism; D005095:Exoribonucleases; D015870:Gene Expression; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics; D051879:Twist-Related Protein 1 / Q000235:genetics; D014746:Vimentin / Q000378:metabolism; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D016271:Proto-Oncogene Proteins c-myc; D051881:Receptor, Notch1; D012097:Repressor Proteins; D014157:Transcription Factors; D051879:Twist-Related Protein 1; D014746:Vimentin; C486307:ZEB1 protein, human; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D000071799:Zinc Finger E-box-Binding Homeobox 1; C487931:mirnlet7 microRNA, human; C117347:DCLK1 protein, human; D000089742:Doublecortin-Like Kinases; D017346:Protein Serine-Threonine Kinases; D005092:Exonucleases; D005095:Exoribonucleases; C413442:SFN protein, human; D018631:ras Proteins