STAT3 and STAT5 Activation in Solid Cancers

Abstract

The Signal Transducer and Activator of Transcription (STAT)3 and 5 proteins are activated by many cytokine receptors to regulate specific gene expression and mitochondrial functions. Their role in cancer is largely context-dependent as they can both act as oncogenes and tumor suppressors. We review here the role of STAT3/5 activation in solid cancers and summarize their association with survival in cancer patients. The molecular mechanisms that underpin the oncogenic activity of STAT3/5 signaling include the regulation of genes that control cell cycle and cell death. However, recent advances also highlight the critical role of STAT3/5 target genes mediating inflammation and stemness. In addition, STAT3 mitochondrial functions are required for transformation. On the other hand, several tumor suppressor pathways act on or are activated by STAT3/5 signaling, including tyrosine phosphatases, the sumo ligase Protein Inhibitor of Activated STAT3 (PIAS3), the E3 ubiquitin ligase TATA Element Modulatory Factor/Androgen Receptor-Coactivator of 160 kDa (TMF/ARA160), the miRNAs miR-124 and miR-1181, the Protein of alternative reading frame 19 (p19ARF)/p53 pathway and the Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3) proteins. Cancer mutations and epigenetic alterations may alter the balance between pro-oncogenic and tumor suppressor activities associated with STAT3/5 signaling, explaining their context-dependent association with tumor progression both in human cancers and animal models.

Keywords: apoptosis; cell cycle; inflammation; mitochondria; solid cancers; stemness; tumor suppression.

Figure 1

Map of somatic mutations detected in human Signal Transducer and Activator of Transcription (STAT)5A, STAT5B and STAT3 in patients with solid cancers. Individual missense mutations found in at least two patients (A), as well as all reported nonsense and frameshift mutations (B), are depicted. Numbers in each box represent the number of cases reported for each mutation. Data were mined from the Catalogue of Somatic Mutations In Cancer (COSMIC) database. ND, N-terminal domain; CCD, Coiled coil domain; DBD, DNA binding domain; LD, Linker domain; SH2, Src homology 2 domain; TAD, Transactivation domain.

Figure 2

Mechanisms of tumorigenic activity of STAT3 and STAT5 signaling in solid tumors.

Figure 3

Tumor suppressor pathways acting on STAT3/5 activity (Protein Inhibitor of Activated STAT3 PIAS, miRNAs, E3 ligases, phosphatases) or activated by STAT3/5 transcriptional activity (Protein of alternative reading frame 19 (p19ARF) Suppressor of Cytokine Signaling 1 and 3 (SOCS1/3), p53). Abbreviations: (PTPN2 (Tyrosine-protein phosphatase non-receptor type 2), PTPN9/MEG2 (Tyrosine-protein phosphatase non-receptor type 9), PTPN11/SHP2 (Tyrosine-protein phosphatase non-receptor type 11), PTPN6/SHP1 (Tyrosine-protein phosphatase non-receptor type 6) and TNF receptor associated factor 6 (TRAF6)).