Difference in the malignancy between RAS and GLI1-transformed astrocytes is associated with frequency of p27KIP1-positive cells in xenograft tissues

Pathol Res Pract. 2021 Jul:223:153465. doi: 10.1016/j.prp.2021.153465. Epub 2021 May 5.

Abstract

We demonstrate that the introduction of GLI1 is sufficient for immortalized human astrocytes to be transformed whereas FOXM1 fails to induce malignant transformation, suggesting differences between GLI1 and FOXM1 in terms of transforming ability despite both transcription factors being overexpressed in malignant gliomas. Moreover, in investigations of mechanisms underlying relatively less-malignant features of GLI1-transformed astrocytes, we found that p27KIP1-positive cells were frequently observed in xenografts derived from GLI1-transformed astrocytes compared to those from RAS-transformed cells. As shRNA-mediated knockdown of p27KIP1 accelerates tumor progression of GLI1-transformed astrocytes, downregulation of p27KIP1 contributes to malignant features of transformed astrocytes. We propose that the models using immortalized/transformed astrocytes are useful to identify the minimal and most crucial set of changes required for glioma formation.

Keywords: Astrocytes; GLI1; Glioma; Transformation; p27(KIP1).

MeSH terms

  • Animals
  • Astrocytes / metabolism*
  • Astrocytes / pathology
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Line, Transformed
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Gene Expression Regulation, Neoplastic
  • Glioma / genetics*
  • Glioma / metabolism
  • Glioma / pathology
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Tumor Burden
  • Zinc Finger Protein GLI1 / genetics*
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • CDKN1B protein, human
  • GLI1 protein, human
  • Zinc Finger Protein GLI1
  • Cyclin-Dependent Kinase Inhibitor p27
  • HRAS protein, human
  • Proto-Oncogene Proteins p21(ras)