DCLK1 facilitates intestinal tumor growth via enhancing pluripotency and epithelial mesenchymal transition

Oncotarget. 2014 Oct 15;5(19):9269-80. doi: 10.18632/oncotarget.2393.

Abstract

Doublecortin-like kinase 1 (Dclk1) is overexpressed in many cancers including colorectal cancer (CRC) andit specifically marks intestinal tumor stem cells. However, the role of Dclk1 in intestinal tumorigenesis in Apc mutant conditions is still poorly understood. We demonstrate that Dclk1 expression and Dclk1+ cells are significantly increased in the intestinal epithelium of elderly ApcMin/+ mice compared to young ApcMin/+ mice and wild type mice. Intestinal epithelial cells of ApcMin/+ mice demonstrate increased pluripotency, self-renewing ability, and EMT. Furthermore, miRNAs are dysregulated, expression of onco-miRNAs are significantly increased with decreased tumor suppressor miRNAs. In support of these findings, knockdown of Dclk1 in elderly ApcMin/+ mice attenuates intestinal adenomas and adenocarcinoma by decreasing pluripotency, EMT and onco-miRNAs indicating that Dclk1 overexpression facilitates intestinal tumorigenesis. Knocking down Dclk1 weakens Dclk1-dependent intestinal processes for tumorigenesis. This study demonstrates that Dclk1 is critically involved in facilitating intestinal tumorigenesis by enhancing pluripotency and EMT factors in Apc mutant intestinal tumors and it also provides a potential therapeutic target for the treatment of colorectal cancer.

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

  • Adenocarcinoma / genetics
  • Adenoma / genetics
  • Adenomatous Polyposis Coli Protein / genetics*
  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Doublecortin-Like Kinases
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / genetics*
  • Intestinal Mucosa / metabolism
  • Intestinal Neoplasms / genetics
  • Intestinal Neoplasms / pathology*
  • Intestines / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • Neoplastic Stem Cells / pathology*
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / genetics*
  • RNA Interference
  • RNA, Small Interfering
  • Spheroids, Cellular
  • Tumor Cells, Cultured

Substances

  • Adenomatous Polyposis Coli Protein
  • MicroRNAs
  • RNA, Small Interfering
  • Doublecortin-Like Kinases
  • Dclk1 protein, mouse
  • Protein Serine-Threonine Kinases