Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma

Cell Signal. 2012 Apr;24(4):852-8. doi: 10.1016/j.cellsig.2011.11.020. Epub 2011 Dec 8.

Abstract

The transcriptional factor Twist1 has been shown to play a key role in regulating epithelial mesenchymal transition, invasiveness and migratory properties in solid tumors. We found that Twist1 is aberrantly expressed in ALK-positive anaplastic large cell lymphoma (ALK+ALCL), a type of T-cell lymphoid malignancy. Using RT-PCR and Western blots, Twist1 was detectable in all 3 ALK+ALCL cell lines examined but absent in normal T-cells. By immunohistochemistry, Twist1 was detectable in all 10 cases of ALK+ALCL examined; benign lymphoid tissues were consistently negative. Twist1 expression in ALK+ALCL cells can be attributed to the NPM-ALK/STAT3 signaling axis, the key oncogenic driving force in this tumor type. Twist1 is biologically important in ALK+ALCL cells, as Twist1 knockdown resulted in a significant decrease in their invasiveness in an in-vitro assay. Further investigation revealed that this increase in invasiveness is linked to the activation of AKT and down-regulation of p66Shc, two signaling proteins known to be involved in NPM-ALK-mediated oncogenesis. Lastly, knockdown of Twist1 sensitizes ALK+ALCL cells to the growth inhibitory effect of PF-2341066 (Crizotinib®), an ALK inhibitor being used in clinical trials. In conclusion, Twist1 expression, owing to the abnormal NPM-ALK/STAT3 signaling, contributes to its invasiveness and decreased sensitivity to PF-2341066 in ALK+ALCL.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crizotinib
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Lymphoma, Large-Cell, Anaplastic* / genetics
  • Lymphoma, Large-Cell, Anaplastic* / metabolism
  • Lymphoma, Large-Cell, Anaplastic* / pathology
  • Neoplasm Invasiveness
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / deficiency
  • Nuclear Proteins / genetics*
  • Piperidines / pharmacology
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrazoles
  • Pyridines / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Shc Signaling Adaptor Proteins / genetics
  • Shc Signaling Adaptor Proteins / metabolism
  • Signal Transduction / genetics*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Twist-Related Protein 1 / antagonists & inhibitors
  • Twist-Related Protein 1 / deficiency
  • Twist-Related Protein 1 / genetics*

Substances

  • Nuclear Proteins
  • Piperidines
  • Pyrazoles
  • Pyridines
  • SHC1 protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Shc Signaling Adaptor Proteins
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • TWIST1 protein, human
  • Twist-Related Protein 1
  • Crizotinib
  • p80(NPM-ALK) protein
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt