STAT1 and STAT3 in tumorigenesis: A matter of balance

Abstract

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.

Keywords: STAT1; STAT3; anti-tumor immune response; apoptosis; inflammation; metastasis; oncogene; proliferation; survival; tumor invasivity; tumor suppressor; tumorigenesis.

Figure 1. Balanced activation and opposite effects of STAT1 and STAT3 in tumor settings. Prevalent STAT3 activation and/or expression, often downstream of IL-6 production, favors tumor development and maintenance. Tumor cell proliferation and survival are favored not only directly, but also indirectly by the maintenance of cancer stem cells and the switch to aerobic glycolysis. STAT3-dependent tumor-produced soluble factors such as IL-10 and VEGF induce STAT3-dependent tolerance in the immune cells. Moreover, STAT3 activation enhances metastasis formation by inducing EMT and cell migration and by increasing tumor angiogenesis. In contrast, the prevalence of STAT1 activation is fundamental to directly and indirectly block cell cycle progression and induce apoptosis of cancer cells. STAT1 elicits an efficient anti-tumor immune response both by stimulating antigen presentation to the immune system and by stimulating immune cells activity. CSCs, cancer stem cells; DC, dendritic cells; EMT, epithelial to mesenchymal transition (modified from ref. 2).