Highlighted STAT3 as a potential drug target for cancer therapy

Abstract

Signal transducer and activator of transcription 3 (STAT3) is a cytoplasmic transcription factor that regulates cell proliferation, differentiation, apoptosis, angiogenesis, inflammation and immune responses. Aberrant STAT3 activation triggers tumor progression through oncogenic gene expression in numerous human cancers, leading to promote tumor malignancy. On the contrary, STAT3 activation in immune cells cause elevation of immunosuppressive factors. Accumulating evidence suggests that the tumor microenvironment closely interacts with the STAT3 signaling pathway. So, targeting STAT3 may improve tumor progression, and anti-cancer immune response. In this review, we summarized the role of STAT3 in cancer and the tumor microenvironment, and present inhibitors of STAT3 signaling cascades. [BMB Reports 2019; 52(7): 415-423].

Fig. 1

STAT3 signaling in cancer. STAT3 signaling is activated by binding of various ligands to their cell surface receptors, leading to phosphorylation of STAT3. STAT3 also directly phosphorylated by Src and Abl, which are non-receptor tyrosine kinases. Phosphorylated STAT3 further homo-dimerized and translocated, to the nucleus. STAT3 regulate CyclinD1, c-Myc, Survivin, Bcl-XL, and Mcl1, which regulate cellular proliferation and survival. STAT3 up-regulates VEGF, bFGF, HGF, and HIF1α. Additionally, STAT3 also regulates MMP2, MMP9, Twist, and Vimentin, for invasion and migration. STAT3 activation also downregulates immune surveillance, by secretion of pro-inflammatory cytokines. Furthermore, maintaining cancer stem cell properties, STAT3 regulates Oct3/4, Nanog, CD133, and CD44.

Fig. 2

The role of STAT3 signaling in the tumor microenvironment. STAT3 signaling supports the communication between tumor cells and the tumor microenvironments. STAT3 drives immunosuppressive effects and tumor promoting effects by endothelial cells and fibroblasts. Activation of STAT3 in dendritic (DC) cells suppresses maturation, activation and antigen presentation which promotes immune tolerance. STAT3 activation in neutrophil, NK cells and effector T cells also has immunosuppressive effects. STAT3 signaling in macrophage favors M2-like polarization and increases PD-L1 expression while STAT3 activation proliferates MDSC population. STAT3 exerts immune tolerance in regulatory T (T_reg) cells by enhancing CTLA4 expression and tumorigenesis in B cells by promoting survival, proliferation and development. STAT3 effect on endothelial cells to promote tumor vascularization. STAT3 in tumor associated fibroblast also enhance tumor metastasis. Collectively, STAT3 signaling is a key regulator of hallmark of cancers.