STAT3

STAT3 stands for "Signal transducer and activator of transcription 3". STAT3 is a transcription factor that is encoded in humans by the gene of the same name. STAT3 is a member of the STAT protein family. Members of this family are phosphorylated by receptor-associated kinases in response to various cytokines and growth factors. They then form homo- or heterodimers that translocate to the nucleus where they act as transcriptional activators.

Notably, STAT3 is considered to be activated upon ligand binding (interferons, epidermal growth factor (EGF), interleukin (IL-)5 and IL-6). In addition, STAT3 activation can occur via phosphorylation of its serine 727 or its tyrosine 705 residue by mitogen-activated protein kinases(MAPK) and by the non-receptor tyrosine kinase c-Src (compound acronym of cellular and sarcoma). STAT3 mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in many cellular processes such as cell growth and apoptosis.

Specifically, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK) in response to cytokines and growth factors, forms homo- or heterodimers, and translocates to the nucleus where it acts as a transcriptional activator. STAT3 mediates the expression of a variety of genes in response to cell stimuli and thus plays a key role in many cellular processes such as cell growth and apoptosis. STAT3-deficient mouse embryos fail to develop beyond embryonic day 7, when gastrulation begins. It appears that at these early developmental stages, activation of STAT3 is required for self-renewal of embryonic stem cells (ESCs).

STAT3 is essential for the differentiation of TH17 helper cells, which have been implicated in a number of autoimmune diseases. Mice lacking STAT3 in T cells show impaired ability to generate T follicular helper (Tfh) cells during viral infection and fail to maintain antibody-based immunity. STAT3 causes upregulation of E-selectin, a factor in cancer metastasis.Thus, Stat3 is a mediator of numerous growth factor and cytokine signaling pathways (Yin W et al 2006). Numerous studies have demonstrated constitutive activation of STAT3 in a variety of human tumors, including hematologic malignancies (leukemias, lymphomas, and multiple myelomas) and diverse solid tumors (such as head and neck, SCC, breast, lung, gastric, hepatocellular, colorectal, and prostate cancers). There is strong evidence that aberrant STAT3 signaling promotes human cancer initiation and progression by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. Suppression of STAT3 activation leads to the induction of apoptosis in tumor cells. Accordingly, STAT3 inhibitors may have potential for the development of new cancer therapies (Siveen KS et al. 2014).

Clinical significance:

Loss-of-function (LOF) mutations in the STAT3 gene result in hyper-IgE syndrome 1, which is associated with recurrent infections and impaired bone and tooth development (Levy DE et al. (2007).

Gain-of -function (GOF) mutations in the STAT3 gene lead to early-onset autoimmune diseases involving multiple organs, such as thyroid disease, diabetes, intestinal inflammation, and low blood counts. A review paper (Fabre A et al. 2019) summarized all available cases with STAT3-GOF mutations. 28 different mutations have been described. Early disease onset with an average age of 3 (0.5-5) years is characteristic of this mutational form. The most common manifestations were.

• autoimmune cytopenias (28 of 42)
• Lymphoproliferation (27 of 42)
• enteropathy (24 of 42)
• interstitial lung disease (15 of 42)
• thyroiditis (13 of 42)
• diabetes (10 of 42) and
• Postnatal growth failure (15 of 21).
• Immunodeficiency was not always a predominant feature.

Most patients required significant immunosuppressive therapy or hematopoietic stem cell transplantation.

Constitutive STAT3 activation is associated with several human cancers. It is and usually associated with poor prognosis. It has both anti-apoptotic and proliferative effects. STAT3 can promote oncogenesis by being constitutively active through various pathways. However, a tumor suppressive role of STAT3 has also been reported. In glioblastoma, STAT3 was shown to have a tumor-promoting or a tumor-suppressive role depending on the mutational background of the tumor. A direct link between the PTEN-Akt-FOXO axis (suppressive) and the Leukemia Inhibitory Factor Receptor beta (LIFRbeta)-STAT3 pathway (oncogenic) has been demonstrated. Increased activity of STAT3 in tumor cells, leads to alterations in the function of protein complexes that control the expression of inflammatory genes, resulting in profound changes in cell phenotypes and their ability to metastasize.

1. Alvarez JV et al (2006) Signal transducer and activator of transcription 3 is required for the oncogenic effects of non-small-cell lung cancer-associated mutations of the epidermal growth factor receptor. Cancer Research 66: 3162-3168.
2. Cao X et al (1996). Activation and association of Stat3 with Src in v-Src-transformed cell lines. Molecular and Cellular Biology 16: 1595-1603.
3. Fabre A et al. (2019) Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review. J Allergy Clin Immunol Pract. 7:1958-1969
4. Kusaba Tet al. (2006) Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncology Reports 15: 1445-1451. doi:10.3892/or.15.6.1445. PMID 16685378.
5. Levy DE et al (2007) STAT3 signaling and the hyper-IgE syndrome." The New England Journal of Medicine. 357: 1655-1658.
6. Olbrich P et al. (2018) STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol 14:1029-1041.
7. Saarimäki-Vire J et al (2017) An Activating STAT3 Mutation Causes Neonatal Diabetes through Premature Induction of Pancreatic Differentiation. Cell Rep 19:281-294.
8. Siveen KS et al (2014) Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta 1845:136-154.
9. Yang XO et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. The Journal of Biological Chemistry 282: 9358-9363.
10. Yin W et al. (2006) Active Stat3 is required for survival of human squamous cell carcinoma cells in serum-free conditions. Molecular Cancer 5:15