Suppressor of cytokine signaling 3 expression in anaplastic large cell lymphoma

Abstract

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%) ALKtumors 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.

Signal Transducer and Activator of Transcription-3: A Molecular Hub for Signaling Pathways in Gliomas

“…SOCS-3 overexpression has been attributed to constitutive STAT-3 activation in various cancers (101,106). However, there are few reports describing SOCS-3 expression in glioblastoma.…”

Gene expression profiling of isolated tumour cells from anaplastic large cell lymphomas: insights into its cellular origin, pathogenesis and relation to Hodgkin lymphoma

“…Only some of them have formerly been shown to be expressed in ALK þ ALCL. 9,22,23 With relaxed filter criteria (FDR p0.2), a few more genes with increased expression in ALK À ALCL were retrieved (not shown), including microRNA155, CD160 and lysozyme. As expected, several genes expressed at higher level in ALK þ ALCL are induced by signalling molecules known to be activated by the ALK-fusion protein, for example the STAT3 targets CD25, SOCS3 (suppressor of cytokine signalling 3) and C/EBPD (CCAAT/enhancerbinding protein delta), the PI3K/Akt targets GAS1 (growth arrest specific 1), paraoxonase 2 and solute carrier family 2, and the Ras target transmembrane protein 158.…”

JunB expression is a common feature of CD30+ lymphomas and lymphomatoid papulosis

“…7,8 For Western blotting, the JunB monoclonal antibody (C-11, Santa Cruz Technology, Santa Cruz, CA, USA) at a 1:200 dilution and the anti-CD30 monoclonal antibody (Ber-H2, Dakocytomation, Carpinteria, CA, USA) at a 1:25 dilution were used. For flow cytometry, a monoclonal CD30 antibody conjugated to phycoerythrin (Immunotech, Westbrook, ME, USA) was used non-diluted.…”