title: Aberrant expression of the transcriptional factor Twist1 promotes invasiveness in ALK-positive anaplastic large cell lymphoma.
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.
authors.affiliation: Department of Surgery, University of Alberta and Cross Cancer Institute, Edmonton, Alberta, Canada; Department of Medical Oncology, The First Hospital of China Medical University, Shen Yang 110001, PR China.
authors.forename: Jingdong
authors.initials: J
authors.lastname: Zhang
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.forename: Fang
authors.initials: F
authors.lastname: Wu
authors.forename: Matthew
authors.initials: M
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Sharon
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ingham
authors.forename: Mary
authors.initials: M
authors.lastname: Hitt
authors.forename: Todd P
authors.initials: TP
authors.lastname: McMullen
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D017728:Lymphoma, Large-Cell, Anaplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles; D011725:Pyridines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D051879:Twist-Related Protein 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*
chemical_list: D009687:Nuclear Proteins; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; C528024:SHC1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D000077547:Crizotinib; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt