The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis

Abstract

Angiogenesis is the development of new blood vessels, which is required for tumor growth and metastasis. Signal transducer and activator of transcription factor 3 (STAT3) is a transcription factor that regulates a variety of cellular events including proliferation, differentiation and apoptosis. Previous studies revealed that activation of STAT3 promotes tumor angiogenesis. In this review, we described the activities of STAT3 signaling in different cell types involved in angiogenesis. Particularly, we elucidated the molecular mechanisms of STAT3-mediated gene regulation in angiogenic endothelial cells in response to external stimulations such as hypoxia and inflammation. The potential for STAT3 as a therapeutic target was also discussed. Overall, this review provides mechanistic insights for the roles of STAT3 signaling in tumor angiogenesis.

Keywords: STAT3; endothelial cells; transcriptional regulation; tumor angiogenesis.

Figure 1. The STAT family members and the STAT3 signaling pathway

(A) A conceptual diagram showing the structure of STAT family members. There are seven members in the STAT family including STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. STAT family members are sharing five highly homologous domains including a N-terminal domain, an STAT_α domain, a DNA-binding domain, an SH2 domain, and a C-terminal domain with transactivation activity. There are some amino acid residues which are crucial for STAT dimerization and transactivation, such as tyrosine 705 (dimerization and DNA binding) and serine 727 (transactivation) residue. These data come from the database of Pfam which belongs to the European Molecular Biology Laboratory-The European Bioinformatics Institute (EMBL-EBI). (http://pfam.xfam.org/protein/P42224/P52630/P40763/Q14765/P42229/P51692/P42226). (B) Schematic depiction of the STAT3 signaling pathway. Extracellular signals including growth factors and cytokines activate STAT3. Binding of these signal factors to their cell surface receptors results in phosphorylation of STAT3 at tyrosine 705 and serine 727. STAT3 monomers then dimerize, binding with each other at the SH2 domain. After translocation into the nucleus, the dimerized STAT3 molecule binds to the promoter region of target genes with or without co-factors, modulating transcription of the genes related to inflammation, cellular proliferation, migration, survival. Unphosphorylated STAT3 monomers also translocate into the nucleus and form a complex with p65 and p50 to regulate NF-κB signal pathway. PKM2 dimers act as a protein kinase to phosphorylate STAT3 at tyrosine 705 in the nucleus.

Figure 2. Mechanisms of transcriptional activation or inhibition of target genes by STAT3

(A) STAT3 dimers activate gene expression with co-factors p300 and HIF-1α. (B) STAT3 is activated by IL-6 and IL-27 in T cells. STAT3 homodimers or heterodimers are translocated into the nucleus and bind to special DNA sequences, initiating gene transcription. (C) STAT3 interacts with co-factors such as STAT1 or SP1 to promote gene expression in stem cells. (D) STAT3 dimers inhibit gene expression by recruiting the DNA methyltransferase DNMT1. (Ac, acetylation; M, methylation; P, phosphorylation; DNMT1, DNA (cytosine-5)-methyltransferase 1; HDAC1, histone deacetylase 1; HIF-1α, hypoxia-inducible factors 1alpha; MMP2, metalloprotease 2; Nur77, nerve growth factor-induced gene B; SHP-1, Src homology region 2 domain-containing phosphatase 1; SP1, specificity protein 1).

Figure 3. Interactions between STAT3 and other proteins

This figure is generated using the website STITCH (http://stitch.embl.de/). The proteins were submitted to the human database. The interactions provided by the database are based on the eight aspects: known interactions encompassing results from curated databases, experimentally determined and predicted interactions gene neighborhood, gene fusions, and gene co-occurrence, textmining, co-expression, and protein homology. Only the proteins relevant to tumor angiogenesis and directly interplaying with STAT3 are shown. (ARNT, aryl hydrocarbon receptor nuclear translocator; CBL, Cbl proto-oncogene, E3 ubiquitin protein ligase; CISH, cytokine inducible SH2-containing protein; C-JUN, jun proto-oncogene; DNMT1, DNA (cytosine-5)-methyltransferase 1; EGFR, epidermal growth factor receptor; EP300, E1A binding protein p300; GRB2, growth factor receptor-bound protein 2; HIF-1α, hypoxia-inducible factor 1 subunit α; HDAC1, histone deacetylase 1; JAK, Janus kinase; MAPK1/3, mitogen-activated protein kinase 1/3; MAP2K1, mitogen-activated protein kinase kinase 1; NDUFA13, NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 13; NIK, NF-κB-inducing kinase; NR4A1, nerve growth factor-induced gene B; PI3K, phosphatidylinositol 3-kinase; PIAS3, protein inhibitor of activated STAT3; RAC1, Ras-related C3 botulinum toxin substrate 1; RBBP4/7, retinoblastoma binding protein 4/7; RELA, v-relreticuloendotheliosis viral oncogene homolog A; SIN3A, SIN3 transcription regulator homolog A; SOCS, suppressors of cytokinesignaling; SOS1, son of sevenless homolog 1; STAT1/3/5A/5B, signal transducers and activators of transcription 1/3/5A/5B; SP1, specificity protein 1; SRC, v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog).

Figure 4. STAT3 in hypoxia-induced angiogenesis

Hypoxia activates STAT3 in both tumor cells and ECs. Under hypoxic conditions, the STAT3/HIF-1α pathway promotes angiogenesis. Crosstalks between ECs and cancer cells also involve in angiogenesis. (ICAM-1, intercellular cell adhesion molecule-1; mTORC1, mammalian target of rapamycin complex 1; Nox4, nicotinamide adenine dinucleotide phosphate oxidase 4; PDGF-B, Platelet-derived growth factor-B; PKR, RNA-dependent protein kinase R; Pyk2, proline-rich tyrosine kinase 2; ROS, reactive oxygen species; Sp1, specificity protein 1).

Figure 5. STAT3 in inflammation-induced angiogenesis

IL-17 promotes IL-6 production in EC and tumor cells, and directly interact with ECs to promote angiogenesis. IL-6 activates STAT3 in tumor cells and ECs to increase expressions of bFGF and VEGF. IL-10 activates STAT3 in inflammatory cells, resulting in the up-regulation of VEGF. IL-19 promotes angiogenesis directly by activating STAT3 in EC and indirectly by stimulating macrophage-released pro-angiogenic factors. (AKT, Protein kinase B; bFGF, basic fibroblast growth factor; GM-CSF, Granulocyte-macrophage colony-stimulating factor; GRO-α also known as CXCL1, C-X-C motif chemokine ligand 1; IL-6, Interleukin 6; IL-10, Interleukin 10; IL-17, Interleukin 17; IL-19, Interleukin 19; JAK, Janus kinases; MMP2, metalloprotease 2; MMP14, metalloprotease 14; MUC 4, Mucin 4; VEGF, vascular endothelial growth factor).

Figure 6. Inhibitors of the STAT3 signaling in tumor angiogenesis

In the process of tumor angiogenesis, the rapid proliferation of tumor cells leads to local hypoxia and inflammation, which activate STAT3 in tumor cells to produce pro-angiogenic factor. VEGF is a potent pro-angiogenic factor to promote EC angiogenesis. The VEGF/VEGFR signal activates STAT3 which subsequently promotes endothelial cell proliferation and migration by regulating the transcription of the targeted genes. Inhibition of STAT3 is a potential therapeutic strategy for tumor growth and angiogenesis. The established inhibitors are shown with the indication of black “T” markers.