DCAMKL-1 regulates epithelial-mesenchymal transition in human pancreatic cells through a miR-200a-dependent mechanism

Cancer Res. 2011 Mar 15;71(6):2328-38. doi: 10.1158/0008-5472.CAN-10-2738. Epub 2011 Feb 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Animals
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Epithelial-Mesenchymal Transition / genetics*
  • Exonucleases / metabolism
  • Exoribonucleases
  • Gene Expression
  • Homeodomain Proteins / genetics
  • Humans
  • Immunohistochemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • Mutation
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Repressor Proteins / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Twist-Related Protein 1 / genetics
  • Vimentin / metabolism
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • 14-3-3 Proteins
  • Biomarkers, Tumor
  • Homeodomain Proteins
  • Intracellular Signaling Peptides and Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • NOTCH1 protein, human
  • Proto-Oncogene Proteins c-myc
  • Receptor, Notch1
  • Repressor Proteins
  • Transcription Factors
  • Twist-Related Protein 1
  • Vimentin
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • mirnlet7 microRNA, human
  • DCLK1 protein, human
  • Protein-Serine-Threonine Kinases
  • Exonucleases
  • Exoribonucleases
  • SFN protein, human
  • ras Proteins