Wingless modulates activator protein-1-mediated tumor invasion

Oncogene. 2019 May;38(20):3871-3885. doi: 10.1038/s41388-018-0629-x. Epub 2019 Jan 25.

Abstract

Metastasis begins with a subset of local tumor cells acquiring the potential to invade into surrounding tissues, and remains to be a major obstacle for cancer treatments. More than 90% of cancer patients died from tumor metastasis, instead of primary tumor growth. The canonical Wnt/β-catenin pathway plays essential roles in promoting tumor formation, yet its function in regulating tumor metastasis and the underlying mechanisms remain controversial. Here we employed well-established Drosophila tumor models to investigate the regulating mechanism of Wingless (Wg) pathway in tumor invasion. Our results showed that Wg signaling is necessary and sufficient for cell polarity disruption-induced cell migration and molecular changes reminiscent of epithelial-mesenchymal transition (EMT). Moreover, reducing Wg signaling suppressed lgl-/-/RasV12-induced tumor invasion, and cooperation between Arm and RasV12 is sufficient to induce tumor invasion. Mechanistically, we found that cell polarity disruption activates JNK signaling, which in turn upregulate wg expression through transcription factor activator protein-1 (AP-1). We identified a consensus AP-1 binding site located in the 2nd intron of wg, and confirmed that it is essential for AP-1 induced wg transcription both in vitro and in vivo. Lastly, we confirmed that the transcriptional activation of WNT by AP-1 is conserved in human cancer cells. These evidences reveal a positive role of Wnt/β-catenin pathway in tumor invasion, and provide a conserved mechanism that connects JNK and Wnt signaling in regulating tumor progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • Animals, Genetically Modified
  • Armadillo Domain Proteins / genetics
  • Armadillo Domain Proteins / metabolism
  • Binding Sites
  • Cell Movement / genetics
  • Cell Polarity
  • Drosophila / cytology
  • Drosophila / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • HeLa Cells
  • Humans
  • IMP Dehydrogenase / genetics
  • IMP Dehydrogenase / metabolism
  • Introns
  • MAP Kinase Signaling System
  • MCF-7 Cells
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / genetics
  • Proto-Oncogene Proteins c-jun / metabolism
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism
  • Wnt Signaling Pathway / physiology
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism*

Substances

  • ARM protein, Drosophila
  • Armadillo Domain Proteins
  • Drosophila Proteins
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Transcription Factor AP-1
  • Transcription Factors
  • Tumor Suppressor Proteins
  • WNT7B protein, human
  • Wnt Proteins
  • Wnt1 Protein
  • fos-related antigen 1
  • l(2)gl protein, Drosophila
  • wg protein, Drosophila
  • IMP Dehydrogenase
  • ras protein, Drosophila