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.