STAT3 signaling in pulmonary arterial hypertension

Figures & data

Table 1. Cancer hallmarks shared with PAH

Cancer hallmarks^32	Evidence found in PAH
Sustained proliferative signaling	• p21 and p27 implication^19^-^23 • Src/STAT3/Pim1 axis activation^28^-^30 • p38/MAPK activation^12^,^13
Evasion from growth suppressors	• p53 is protective against PAH^19 and p53 expression is downregulated in monocrotaline model of PAH^23 • impaired function of SMAD pathways^9^,^10
Active invasion and metastasis	None
Replicative immortality	None
Angiogenesis	Plexiform lesion^6^,^18
Resistance to cell death	• Bad phosphorylation^33 • Increased Bcl2 expression,^26 • Mitochondrial membrane hyperpolarization^34
Avoided immune destruction	None
Tumor promoting inflammation	Increased level of pro-inflammatory cytokines^8
Genome instability and mutation	• Morphogenetic protein receptor 2 (BMPR2) mutation^9^,^11 • Activin-like kinase 1 (ALK1) mutation • Polymorphisms found in the sequence coding for the serotonin transporter 5-HTT and the gene KCNA5 coding for the potassium channel Kv1.5^17
Deregulated cellular energetic	Warburg effect^24^,^25

Figure 1. Spectrum of STAT3 implication in PAH. STAT3 is activated in response to cytokines, growth factors and agonists that are dysregulated in PAH, signal transduction trough their receptors (tyrosine kinase, G-protein-coupled, immunoglobin like or integrin), and involvement of SHP2 and Src. STAT3 activates a broad range of transcription factors and proteins, all implicated in the management of proliferation and resistance to apoptosis that lead to the development of PAH. By downregulating miR-204, STAT3 abolishes SHP2 repression, enhances Src activation and finally sustains its own activation. Several STAT3 inhibitors (in red) might be beneficial for the treatment of PAH. Some of them are in early phase clinical trial for the treatment of cancer. This might as well facilitate their utilization for PAH treatment as data on their tolerability and efficiency will be available soon. DHEA is actually undergoing a phase 3 clinical trials for chronic obstructive pulmonary diseases and pulmonary hypertension.

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