DCAMKL-1 Regulates Epithelial-mesenchymal Transition in Human Pancreatic Cells Through a MiR-200a-dependent Mechanism

Overview

Journal Cancer Res

Specialty Oncology

Date 2011 Feb 3

PMID 21285251

Citations 130

Authors

Sripathi M Sureban

Randal May

Stan A Lightfoot

Aimee B Hoskins

Megan Lerner

Daniel J Brackett

Russell G Postier

Rama Ramanujam

Altaf Mohammed

Chinthalapally V Rao

James H Wyche

Shrikant Anant

Courtney W Houchen

Affiliations

Soon will be listed here.

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.

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