STAT6: A review of a signaling pathway implicated in various diseases with a special emphasis in its usefulness in pathology

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Abstract

Signal Transducer and Activator of Transcription 6 (STAT6), belonging to a family of seven similar members is primarily stimulated by interleukin(IL)-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing factor. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but also in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and primary central nervous system lymphoma, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous tumor, despite not directly responsible for the tumorigenic effect. These pathophysiological implications of the STAT6 pathway, its diagnostic or prognostic role in pathology, as well its immunohistochemical detection with different antibodies will be discussed in this review.

Introduction

Signal Transducer and Activator of Transcription 6 (STAT6) belongs to a family of transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) showing similar structure and function [1,2]. STAT6 is primarily stimulated by IL-4 and IL-13, and acts as a T helper type 2 (Th2)-inducing transcriptional activator [1,2]. Thus, it is implicated in the pathophysiology of various allergic conditions, such as asthma, atopic dermatitis, eosinophilic esophagitis and food allergies, but it is also involved in various tumors development, primarily lymphomas and solitary fibrous tumors, while it participates in the regulation of the tumor microenvironment.

Thus, this review aims to present the main diseases where the STAT6 pathway is implicated, explaining its function and probable diagnostic or prognostic significance in the different settings.

Section snippets

STAT6 pathway

STAT6 maps to 12q13.3-q14.1 in very close proximity to the NAB2 gene, which codes for a transcriptional repressor [3]. STAT6 signaling pathway activation demands its phosphorylation. STAT6 is primarily stimulated by IL-4 and IL-13, but other cytokines, such as IL-3, IL-15, interferon(IFN)α, or growth factors, such as platelet-derived growth factor (PDGF), can activate it [1]. The signaling cascade of the STAT6 pathway starts with the engagement of cytokine receptors [3]. When these cytokines

STAT6 functions

STAT6 is a critical molecule in regulating immune responses and it is implicated in the development of allergic conditions [2,4], and in efficient immunity to helminthic parasites [2], since intact STAT6 T cell signaling is required for helminth-associated intestinal inflammation [5].

One of the cornerstones in its role in inflammation, is its effects in T cells. STAT6 regulates T-cell proliferation by decreasing the expression of CDKN1B, and the Th2 differentiation by controlling the expression

STAT6 and lymphomas

Hodgkin and Reed-Sternberg cells in classical Hodgkin lymphoma and lymphocytic and histiocytic cells in nodular lymphocyte–predominant Hodgkin lymphoma recruit the reactive cells of their microenvironment and they induce their own autocrine stimulation by expressing cytokines, most of which act through the JAK-STAT pathway [10]. STAT6 is activated in Hodgkin and Reed-Stenberg cells (Fig. 1) by an IL13-IL13 receptor autocrine feedback loop [10]. It should be also noted that

STAT6 and solitary fibrous tumor

Solitary fibrous tumor (SFT, Figs. 10, 11), a mesenchymal tumor of fibroblastic differentiation, is mainly a pleural tumor [31,32], but it can arise virtually all over the body, including the central nervous system, the dermis/subcutis, the head and neck region, the breast and the female gynecologic organs [[33], [34], [35], [36], [37], [38]]. Most SFT are benign, with approximately 10 % showing local recurrences and 5% a malignant behavior, which is difficult to predict in histology basis only

STAT6 and allergic/inflammatory conditions

Asthma, allergic rhinitis, and atopic dermatitis, as well as food allergies and eosinophilic esophagitis are considered as Th2 cell-mediated diseases, and STAT6 induces Th2 cell-mediated allergic diseases [54]. Certain STAT6 polymorphisms are associated with increased risk for asthma development [55]. Considering asthma pathophysiology, STAT6 induces Sonic hedgehog expression in airway epithelium, leading to goblet cell metaplasia and increased mucous secretion [56]. Also, pSTAT6 seems to be

STAT6 and immune microenvironment of cancer

STAT6 is implicated in tumor micro-environment mainly through its role in inducing the production of pro-tumoral macrophages. Tumor-associated macrophages are induced by IL4 and IL6, through STAT6 and STAT3, to provide pro-tumoral properties, and to achieve immunosuppressive properties in nearby T cells in a PD-L1 dependent manner [60]. Consistent with these findings, M2 tumor-associated macrophages predominate at metastatic sites, where they facilitate metastatic process through activation of

Conclusion

STAT6 is an important factor regulating Th2 responses and as such is implicated in allergic conditions and in tumor microenvironment regulation. Furthermore, certain forms of lymphomas, notably the Hodgkin lymphoma group, the primary mediastinal and central nervous system lymphomas, as well as some follicular and T cell lymphomas are associated with dysregulation of the STAT6 pathway. STAT6 immunohistochemical expression also serves as a surrogate marker in the diagnosis of solitary fibrous

Declaration of Competing Interest

The authors report no declarations of interest.

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