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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Blotting, Western
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crizotinib
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Gene Expression Regulation, Neoplastic*
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Gene Knockdown Techniques
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Humans
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Immunohistochemistry
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Lymphoma, Large-Cell, Anaplastic* / genetics
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Lymphoma, Large-Cell, Anaplastic* / metabolism
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Lymphoma, Large-Cell, Anaplastic* / pathology
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Neoplasm Invasiveness
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics*
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Piperidines / pharmacology
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles
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Pyridines / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Shc Signaling Adaptor Proteins / genetics
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Shc Signaling Adaptor Proteins / metabolism
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Signal Transduction / genetics*
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Twist-Related Protein 1 / antagonists & inhibitors
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Twist-Related Protein 1 / deficiency
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Twist-Related Protein 1 / genetics*
Substances
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Nuclear Proteins
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Piperidines
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Pyrazoles
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Pyridines
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SHC1 protein, human
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STAT3 Transcription Factor
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STAT3 protein, human
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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TWIST1 protein, human
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Twist-Related Protein 1
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Crizotinib
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p80(NPM-ALK) protein
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-akt