Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma.
Using a cDNA microarray, we found that suppressor of cytokine signaling 3 (SOCS3) is highly expressed in anaplastic lymphoma kinase (ALK)+ anaplastic large cell lymphoma (ALCL) cell lines. As SOCS3 is induced by activated signal transducer and activator of transcription 3 (STAT3), and ALK activates STAT3, we hypothesized that SOCS3 may play a role in ALK+ ALCL pathogenesis via the Janus kinase 3 (JAK3)-STAT3 pathway. Using ALCL cell lines, we show by coimmunoprecipitation experiments that SOCS3 physically binds with JAK3 in vitro, and that JAK3 inhibition by WHI-P154 downregulates SOCS3 expression. Western blot analysis confirmed expression of SOCS3 and also showed coexpression of phosphorylated (activated) STAT3 (pSTAT3). Direct sequencing of the SOCS3 gene showed no mutations or alternative splicing. In ALCL tumors that were assessed by immunohistochemistry, nine of 12 (75%) ALK+ tumors were SOCS3 positive and eight (67%) coexpressed pSTAT3. In comparison, 18 of 25 (72%) ALK-- tumors were SOCS3 positive and seven (28%) coexpressed pSTAT3. These results show that SOCS3 is overexpressed in ALCL, attributable to JAK3-STAT3 activation and likely related to ALK in ALK+ tumors. However, SOCS3 is also expressed in tumors that lack STAT3 and ALK suggesting alternative mechanisms of upregulation.
Cho-Vega
J H
JH
Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Rassidakis
G Z
GZ
Amin
H M
HM
Tsioli
P
P
Spurgers
K
K
Remache
Y K
YK
Vega
F
F
Goy
A H
AH
Gilles
F
F
Medeiros
L Jeffrey
LJ
D017398:Alternative Splicing; D000077548:Anaplastic Lymphoma Kinase; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D053616:Janus Kinase 3; D017728:Lymphoma, Large-Cell, Anaplastic / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011799:Quinazolines; D012097:Repressor Proteins; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C113888:WHI P154; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3