DNp73 exerts function in metastasis initiation by disconnecting the inhibitory role of EPLIN on IGF1R-AKT/STAT3 signaling

Cancer Cell. 2013 Oct 14;24(4):512-27. doi: 10.1016/j.ccr.2013.08.023.

Abstract

Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytoskeletal Proteins / metabolism*
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Mice, Nude
  • Neoplasm Metastasis
  • Neoplasm Transplantation
  • Nuclear Proteins / metabolism
  • Nuclear Proteins / physiology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, IGF Type 1 / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Tumor Protein p73
  • Tumor Suppressor Protein p53 / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cytoskeletal Proteins
  • D15Ertd366e protein, mouse
  • DNA-Binding Proteins
  • LIMA1 protein, human
  • Nuclear Proteins
  • STAT3 Transcription Factor
  • TP53 protein, human
  • TP73 protein, human
  • Trp73 protein, mouse
  • Tumor Protein p73
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt