TAp63-Regulated miRNAs Suppress Cutaneous Squamous Cell Carcinoma through Inhibition of a Network of Cell-Cycle Genes

Cancer Res. 2020 Jun 15;80(12):2484-2497. doi: 10.1158/0008-5472.CAN-19-1892. Epub 2020 Mar 10.

Abstract

TAp63 is a p53 family member and potent tumor and metastasis suppressor. Here, we show that TAp63-/- mice exhibit an increased susceptibility to ultraviolet radiation-induced cutaneous squamous cell carcinoma (cuSCC). A human-to-mouse comparison of cuSCC tumors identified miR-30c-2* and miR-497 as underexpressed in TAp63-deficient cuSCC. Reintroduction of these miRNAs significantly inhibited the growth of cuSCC cell lines and tumors. Proteomic profiling of cells expressing either miRNA showed downregulation of cell-cycle progression and mitosis-associated proteins. A mouse to human and cross-platform comparison of RNA-sequencing and proteomics data identified a 7-gene signature, including AURKA, KIF18B, PKMYT1, and ORC1, which were overexpressed in cuSCC. Knockdown of these factors in cuSCC cell lines suppressed tumor cell proliferation and induced apoptosis. In addition, selective inhibition of AURKA suppressed cuSCC cell proliferation, induced apoptosis, and showed antitumor effects in vivo. Finally, treatment with miR-30c-2* or miR-497 miRNA mimics was highly effective in suppressing cuSCC growth in vivo. Our data establish TAp63 as an essential regulator of novel miRNAs that can be therapeutically targeted for potent suppression of cuSCC. SIGNIFICANCE: This study provides preclinical evidence for the use of miR-30c-2*/miR-497 delivery and AURKA inhibition in the treatment of cuSCC, which currently has no FDA-approved targeted therapies.See related commentary by Parrales and Iwakuma, p. 2439.

Publication types

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

MeSH terms

  • Animals
  • Aurora Kinase A / genetics
  • Carcinoma, Squamous Cell* / genetics
  • Cell Proliferation / genetics
  • Humans
  • Kinesin
  • Membrane Proteins
  • Mice
  • MicroRNAs* / genetics
  • Protein-Serine-Threonine Kinases
  • Protein-Tyrosine Kinases
  • Proteomics
  • Skin Neoplasms* / genetics
  • Ultraviolet Rays

Substances

  • MIRN497 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Protein-Tyrosine Kinases
  • AURKA protein, human
  • Aurora Kinase A
  • PKMYT1 protein, human
  • Protein-Serine-Threonine Kinases
  • KIF18B protein, human
  • Kinesin