Overexpression of REIC/Dkk-3 in normal fibroblasts suppresses tumor growth via induction of interleukin-7

J Biol Chem. 2009 May 22;284(21):14236-44. doi: 10.1074/jbc.M808002200. Epub 2009 Mar 11.


We previously showed that the tumor suppressor gene REIC/Dkk-3, when overexpressed by an adenovirus (Ad-REIC), exhibited a dramatic therapeutic effect on human cancers through a mechanism triggered by endoplasmic reticulum stress. Adenovirus vectors show no target cell specificity and thus may elicit unfavorable side effects through infection of normal cells even upon intra-tumoral injection. In this study, we examined possible effects of Ad-REIC on normal cells. We found that infection of normal human fibroblasts (NHF) did not cause apoptosis but induced production of interleukin (IL)-7. The induction was triggered by endoplasmic reticulum stress and mediated through IRE1alpha, ASK1, p38, and IRF-1. When Ad-REIC-infected NHF were transplanted in a mixture with untreated human prostate cancer cells, the growth of the cancer cells was significantly suppressed. Injection of an IL-7 antibody partially abrogated the suppressive effect of Ad-REIC-infected NHF. These results indicate that Ad-REIC has another arm against human cancer, an indirect host-mediated effect because of overproduction of IL-7 by mis-targeted NHF, in addition to its direct effect on cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adenoviridae
  • Animals
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokines
  • Endoplasmic Reticulum / pathology
  • Fibroblasts / enzymology
  • Fibroblasts / metabolism*
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Interferon Regulatory Factor-1 / metabolism
  • Interleukin-7 / metabolism*
  • MAP Kinase Kinase Kinase 5 / metabolism
  • Mice
  • Neoplasms / pathology*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Adaptor Proteins, Signal Transducing
  • Chemokines
  • DKK3 protein, human
  • IRF1 protein, human
  • Intercellular Signaling Peptides and Proteins
  • Interferon Regulatory Factor-1
  • Interleukin-7
  • STAT1 Transcription Factor
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinase 5
  • MAP3K5 protein, human