In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3

Abstract

A characteristic feature of neoplastic transformation is a perpetual activation of oncogenic proteins. Here, we studied signal transducers and activators of transcription (STAT) in patients with mycosis fungoides (MF)/cutaneous T-cell lymphoma (CTCL). Malignant lymphocytes in dermal infiltrates of CTCL tumors showed frequent and intense nuclear staining with anti-PY-STAT3 antibody, indicating a constitutive activation of STAT3 in vivo in tumor stages. In contrast, only sporadic and faint staining was observed in indolent lesions of patch and plaque stages of MF. Moreover, neoplastic lymphocytes in the epidermal Pautrier abscesses associated with early stages of MF did not express activated STAT3. To address the role of STAT3 in survival/apoptosis, CTCL tumor cells from an advanced skin tumor were transfected with either wild-type STAT3 (STAT3wt) or dominant-negative STAT3 (STAT3D). Forced inducible expression of STAT3D triggered a significant increase in tumor cells undergoing apoptosis, whereas forced expression of STAT3wt or empty vector had no effect. In conclusion, a profound in vivo activation of STAT3 is observed in MF tumors but not in the early stages of MF. Moreover, STAT3 protects tumor cells from apoptosis in vitro. Taken together, these findings suggest that STAT3 is a malignancy factor in CTCL.

STAT5-mediated expression of oncogenic miR-155 in cutaneous T-cell lymphoma

“…40 Both STAT3 and NFkB are known to be constitutively activated in CTCL. 26,27,41 Likewise, we observed expression of the active form of STAT5 (pY-STAT5) in malignant T cells in situ and in cell lysates from malignant T cell lines (Fig. S1A-D and E, respectively), confirming and extending other studies, 35 and suggesting that STAT5 is constitutively activated in CTCL.…”

“…In line with the results from STATs, resulting in malignant cell proliferation and survival. [23][24][25] In advanced disease, malignant T cells display a cytokine-independent, constitutive activation of JAK3, which drives a constitutive activation of STAT3 that, in turn, increases survival and resistance to apoptosis in malignant T cells, 26,27 and induces production of cytokines involved in eosinophilia and erythroderma (IL-5), as well as T helper 2 (Th2), 28 and Th17 29 cytokines. Furthermore, the pathway is believed to play a role in creating a pro-oncogenic inflammatory environment via production of VEGF 30 and IL-10 31 and induction of suppressor of cytokine signaling-3 (SOCS-3), 32 which confers resistance to IFNα in malignant T cells.…”

Cutaneous T‐cell lymphoma: 2011 update on diagnosis, risk‐stratification, and management

“…Nuclear localization and DNA-binding of phosphorylated STAT3 has been convincingly demonstrated in CTCL [77,78]. Following nuclear translocation, STAT3 directly regulates a number of target genes in CTCL, including regulators of apoptosis (e.g., Bcl-2/Bax), cytokines (e.g., IL-5, IL-13) and suppressors of cytokine signaling (e.g., SOCS).…”

IFN Regulatory Factor-2 Regulates Macrophage Apoptosis through a STAT1/3- and Caspase-1-Dependent Mechanism

“…The relationship between STAT3 activation and apoptosis has been explored previously (53,(63)(64)(65)(66). For example, STAT3 has been shown to repress apoptosis by inhibiting caspase-3 and up-regulating Bcl-x L (14).…”

“…Most of these differentially expressed genes were found by TraFac to contain putative STAT binding sites, and therefore, could theoretically be affected by fluctuations in STAT protein levels as a result of IRF-2 deficiency. Among the genes identified as being down-regulated in the absence of IRF-2, we selected Stat3 to examine for its potential role in IRF-2-dependent apoptosis, given its already wellcharacterized role in apoptosis regulation (15,52,53).…”