KLF4 Is Essential for Induction of Cellular Identity Change and Acinar-to-Ductal Reprogramming during Early Pancreatic Carcinogenesis

Cancer Cell. 2016 Mar 14;29(3):324-338. doi: 10.1016/j.ccell.2016.02.005.

Abstract

Understanding the molecular mechanisms of tumor initiation has significant impact on early cancer detection and intervention. To define the role of KLF4 in pancreatic ductal adenocarcinoma (PDA) initiation, we used molecular biological analyses and mouse models of klf4 gain- and loss-of-function and mutant Kras. KLF4 is upregulated in and required for acinar-to-ductal metaplasia. Klf4 ablation drastically attenuates the formation of pancreatic intraepithelial neoplasia induced by mutant Kras(G12D), whereas upregulation of KLF4 does the opposite. Mutant KRAS and cellular injuries induce KLF4 expression, and ectopic expression of KLF4 in acinar cells reduces acinar lineage- and induces ductal lineage-related marker expression. These results demonstrate that KLF4 induces ductal identity in PanIN initiation and may be a potential target for prevention of PDA initiation.

Publication types

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

MeSH terms

  • Acinar Cells / metabolism
  • Acinar Cells / pathology*
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Carcinoma, Pancreatic Ductal / genetics
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Genes, ras / genetics
  • Humans
  • Kruppel-Like Transcription Factors / metabolism*
  • Mice
  • Pancreas / metabolism
  • Pancreas / pathology*
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / pathology*
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology
  • Up-Regulation / genetics

Substances

  • GKLF protein
  • Kruppel-Like Transcription Factors