Gabriella Regis

Ups and downs: The STAT1:STAT3 seesaw of Interferon and gp130 receptor signalling

Downstream of cytokine or growth factor receptors, STAT3 counteracts inflammation and promotes cell survival/proliferation and immune tolerance while STAT1 inhibits proliferation and favours innate and adaptive immune responses. STAT1 and STAT3 activation are reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may re-direct cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non-canonical effects of STAT1/3 activation and discuss the hypothesis that perturbation of their expression and/or activation levels may provide novel therapeutic strategies in different clinical settings and particularly in cancer.

STAT1 and STAT3 in tumorigenesis: A matter of balance

The transcription factors STAT1 and STAT3 appear to play opposite roles in tumorigenesis. While STAT3 promotes cell survival/proliferation, motility and immune tolerance and is considered as an oncogene, STAT1 mostly triggers anti-proliferative and pro-apoptotic responses while enhancing anti-tumor immunity. Despite being activated downstream of common cytokine and growth factor receptors, their activation is reciprocally regulated and perturbation in their balanced expression or phosphorylation levels may re-direct cytokine/growth factor signals from proliferative to apoptotic, or from inflammatory to anti-inflammatory. Here we review the functional canonical and non-canonical effects of STAT1 and STAT3 activation in tumorigenesis and their potential cross-regulation mechanisms.

Constitutive STAT3 activation in epidermal keratinocytes enhances cell clonogenicity and favours spontaneous immortalization by opposing differentiation and senescence checkpoints.

STAT3, a pleiotropic transcription factor acting downstream of cytokines and growth factors, is known to enhance proliferation, migration, invasion and aerobic glycolysis in tumors upon aberrant activation. In the murine epidermis, STAT3 is necessary for experimentally induced carcinogenesis. Skin tumorigenesis is conversely enhanced by overexpression in keratinocytes of the constitutively active STAT3C mutant, which also induces robust, psoriasis‐like epidermal hyperplasia. We show here that STAT3C expression at physiological levels in knock‐in mice leads to mild epidermal hyperplasia and attenuated expression of terminal differentiation markers. Altered differentiation is confirmed in isolated primary epidermal keratinocytes in vitro, correlating with enhanced proliferative and clonogenic potential, attenuated senescence and, strikingly, high‐frequency spontaneous immortalization. These results suggest that moderate levels of continuous STAT3 activation, which closely resemble those triggered by chronic inflammation or persistent growth factor stimulation, may establish a preneoplastic state in part by promoting the escape of epidermal progenitor cells from differentiation and senescence checkpoints.

Universal and Specific Functions of STAT3 in Solid Tumours

STAT3 is constitutively activated in a high percentage of tumours and tumour-derived cells of both liquid and solid origin, often correlating with aggressive disease and bad prognosis. Persistent STAT3 activity, to which tumours often become addicted, is mostly due to the aberrant activation of pro-oncogenic/pro-inflammatory signals that can trigger its phosphorylation, such as oncogenes, growth factor receptors and cytokines. Among STAT3-mediated functions are increased survival and proliferation, enhanced angiogenesis, motility and invasion, and down-modulation of anti-tumour immune responses. Moreover, STAT3 was recently shown to play unexpected roles in regulating cell metabolism and mitochondrial activity via both transcriptional and non-transcriptional mechanisms. Here, we review the main knowledge about the role of STAT3 in solid tumours, with a particular focus on breast cancer and our recent work with mouse models.