STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma

Brender, Christine; Nielsen, Mette; Kaltoft, Keld; Mikkelsen, Gitte; Zhang, Qian; Wasik, Mariusz A.; Billestrup, Nils; Ødum, Niels

doi:10.1182/blood.v97.4.1056

Cited by 118 publications

(93 citation statements)

References 36 publications

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“…Our data supports previous studies demonstrating constitutive expression of STAT3 in CTCL cell lines, [10][11][12][13][14][15][16][17][18][19] and confirm findings in a recent report that showed constitutive and sustained ex vivo expression of pSTAT3 over 24 h in PBMCs from a group of four SS/MF patients. 18 In contrast, an earlier study documented strong expression of pSTAT3 in only 2 out of 14 SS patients.…”

Section: Discussionsupporting

confidence: 82%

“…The SOCS family of negative STAT regulators is also unlikely to mediate aberrant STAT3 activation in SS, as it has been reported that SOCS3 is expressed at high levels in CTCL cell lines and SS patients. 19 Moreover, the use of a dominantnegative STAT3 in CTCL cell lines was shown to downregulate constitutive expression of SOCS3, demonstrating that SOCS3 expression is a consequence rather than a mediator of aberrant STAT3 activation. Furthermore, no SOCS3-associated mutations have been identified in CTCL.…”

Section: Discussionmentioning

confidence: 99%

“…9 Constitutive activation of STAT3 has been demonstrated in studies of cell lines derived from MF and SS patients and anaplastic large cell lymphoma. [10][11][12][13][14][15][16][17][18][19] In lesional patient-derived material, strong expression of pSTAT3 has been identified by immunohistochemistry in tumour biopsy samples from advanced stage MF patients, but only weak expression was detected in early patch/plaque lesions. 11 In SS patients, the activation status of STAT3 is less clear, with one study demonstrating the strong expression of pSTAT3 in peripheral blood mononuclear cells (PBMCs) from only 2 of 14 patients.…”

Section: Introductionmentioning

confidence: 99%

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Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sé zary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4 þ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylationspecific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan-JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2-activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

et al. 2011

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“…[7][8][9] In later stages of the disease, the malignant T cells show aberrant hyperactivation of Janus kinase-3 (Jak3) 10 and signal tranducers and activators of transcription (STAT) 11,12 proteins, which in turn trigger survival signals and the expression of suppressor of cytokine signalling-3 (SOCS3). 13 SOCS3 protects the malignant T cells from inhibition by IFNs 13 and is a marker of a poor prognosis. 14 During disease progression, the normal T-cell compartment is depleted and the immune system becomes increasingly compromised, leading to a state of immunodeficiency.…”

Section: Introductionmentioning

confidence: 99%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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Sé zary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-b and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-jB (NF-jB) activity in reporter assays which is in keeping with a constitutive NF-jB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.

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“…Persistent expression of SOCS1 and/or SOCS3 is observed in several haematological malignancies. Such as cutaneous T cell lymphoma, chronic myeloid leukemia, ALK+ anaplastic large cell lymphoma and some acute leukemia (Schuringa et al, 2000;Brender et al, 2001;Sakai et al, 2002;Cho-Vega et al, 2004;Roman-Gomaz et al, 2004). Also, in patients with colorectal cancer, papillary thyroid cancer, glioblastoma primary tissues, breast cancer and hepatocellular carcinoma tumors protein expression of SOCS1 and SOCS3 (Sasi et al, 2010;Wu et al, 2011;Ayyildiz et al, 2014;Kobawala et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Clinical Relevance of SOCS1 and SOCS3 in Patients with Oral Squamous Cell Carcinoma

Trivedi¹,

Kobawala²,

Ghosh³

et al. 2017

AJCRCO

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Though Suppressors of Cytokine Signaling (SOCS) proteins are known for negative feedback regulators of cytokine signaling their role in cancer is controversial. In the current study we sought to explore the occurrence of SOCS1 and SOCS3 in oral squamous cell carcinoma (OSCC) patients and evaluate their potential relationship with clinicopathological parameters and disease outcome. Using immunohistochemistry protein expression of SOCS1 and SOCS3 were evaluated from paraffin embedded primary OSCC tumors of 61 patients. Scoring was done by semiquantitative method. Cytoplasmic expression of SOCS1 and SOCS3 was noted in 54% and 59% of OSCC patients, respectively. Overexpression of SOCS1 was found to be significantly correlated with nodal status (p=0.020), disease stage (P = 0.014), histological grade (p=0.032) and lymphatic permeation (p=0.0001). SOCS3 showed significant association with nodal status (p=0.011), disease stage (p =0.009), lymphatic (p=0.0001) and vascular permeation (p=0.002). Kaplan-Meier curves for relapse-free survival (RFS) and overall survival (OS) demonstrated that SOCS3 remained significant indicator for predicting reduced RFS (Log rank=6.21, p=0.0127) and worse OS (Log rank=4.49, p=0.0340) for OSCC patients. However, in multivariate analysis it failed to reach at statistically significant. Our study found upregulated protein expression of SOCS1 and SOCS3 in advanced stage of OSCC patients having aggressive tumor phenotype. Therefore, study of SOCS1 and SOCS3 might be useful for precisely identifying high risk OSCC patients for more effective tailored treatment.

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STAT3-mediated constitutive expression of SOCS-3 in cutaneous T-cell lymphoma

Cited by 118 publications

References 36 publications

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

Constitutive activation of STAT3 in Sézary syndrome is independent of SHP-1

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Clinical Relevance of SOCS1 and SOCS3 in Patients with Oral Squamous Cell Carcinoma

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