Mutant Kras-induced upregulation of CD24 enhances prostate cancer stemness and bone metastasis

Oncogene. 2019 Mar;38(12):2005-2019. doi: 10.1038/s41388-018-0575-7. Epub 2018 Nov 22.

Abstract

Prostate cancer (PCA), one of the most common malignant tumors in men, is the second leading cause of cancer deaths in males worldwide. We report here that PCA models harboring conditional LSL/KrasG12D or BRAFF-V600E allele with prostate-specific abrogated p53 function recapitulate human PCA precursor lesions, histopathology, and clinical behaviors. We found that the development of reprogrammed EMT-like phenotypes and skeleton metastatic behavior requires concurrent activated Kras and p53 depletion in PCA. Microarray analyses of primary PCA cells derived from these models identified several cancer stemness genes including CD24, EpCAM, and CD133 upregulated by KRASG12D. Among these stemness markers, we identified CD24 as a key driver of tumorigenesis and metastasis in vivo. These data demonstrate that specific factors involved in cancer stemness are critical for metastatic conversion of PCA and may be ideal targets for therapeutic intervention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Neoplasms / secondary*
  • CD24 Antigen / genetics*
  • Carcinogenesis / genetics
  • Cell Movement / genetics
  • Cell Proliferation / genetics
  • Cell Shape / genetics
  • Gene Knockdown Techniques
  • Humans
  • Male
  • Mice
  • Mutation*
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / pathology*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Signal Transduction / genetics
  • Tumor Suppressor Protein p53 / deficiency
  • Up-Regulation / genetics*

Substances

  • CD24 Antigen
  • KRAS protein, human
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins p21(ras)