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ΔNp63α is a common inhibitory target in oncogenic PI3K/Ras/Her2-induced cell motility and tumor metastasis

Linshan Hu1, Shan Liang1,2, Hu Chen1

  • 1Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, State Key Laboratory of Biotherapy, College of Life Sciences, Sichuan University, Chengdu, Sichuan 610064, China.

Proceedings of the National Academy of Sciences of the United States of America
|May 5, 2017
PubMed

Insights

Oncogenic mutations in PI3K, Ras, and Her2 signaling suppress the tumor-suppressing protein ΔNp63α, promoting cancer metastasis. Restoring ΔNp63α expression inhibits this process, highlighting its role in controlling cancer spread.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Activation of phosphatidylinositol 3 kinase (PI3K), Ras, and Her2 signaling pathways is crucial in cancer development.
  • Hotspot mutations in oncogenes like PIK3CA and RAS, and Her2 overexpression, are common in human tumors.
  • Decreased expression of ΔNp63α, a key p63 protein isoform, is linked to cancer metastasis.

Purpose of the Study:

  • To investigate the role of oncogenic PI3K, Ras, and Her2 signaling in regulating ΔNp63α expression.
  • To determine if ΔNp63α can counteract the pro-metastatic effects of these oncogenes.
  • To elucidate the molecular mechanism linking oncogenic signaling, ΔNp63α, and cancer metastasis.

Main Methods:

  • Utilized cell lines with specific oncogenic mutations (p110αH1047R, K-RasG12V, H-RasG12V) and Her2 activation.
  • Investigated the effect of these oncogenic activations on ΔNp63α expression and cell motility.
  • Employed Akt-fork-head transcription factor 3a (Akt-FOXO3a) signaling pathway analysis.
  • Performed in vitro cell motility assays and in vivo tumor metastasis mouse models.
  • Analyzed the direct transcriptional targeting of ΔNp63α by FOXO3a.
  • Correlated FOXO3a and ΔNp63α expression in human cancer biopsy samples.

Main Results:

  • Oncogenic mutations in PIK3CA and RAS, and Her2 activation, suppressed ΔNp63α expression through the Akt-FOXO3a pathway.
  • This suppression led to increased cell motility and tumor metastasis.
  • Restoration of ΔNp63α expression reversed the enhanced cell motility and metastasis induced by these oncogenes.
  • ΔNp63α was identified as a direct transcriptional target of FOXO3a.
  • FOXO3a and ΔNp63α expression levels were correlated in human cancer samples.

Conclusions:

  • ΔNp63α acts as a common inhibitory target for oncogenic PI3K, Ras, and Her2 signaling.
  • The Akt-FOXO3a-ΔNp63α axis is a critical mediator of oncogene-driven cancer metastasis.
  • ΔNp63α functions as a key integrator of oncogenic signals that control cancer cell motility and metastasis.
Keywords:
Her2PIK3CARascancer metastasisΔNp63α

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