A new study has shown that the signal transducer and activator of the transcription 3 (STAT3) gene influences the course of disease in cystic fibrosis (CF) by affecting cystic fibrosis transmembrane conductance regulator (CFTR) protein expression. The study, published in Human Molecular Genetics, found that the inhibition of STAT3 resulted in greater expression of CFTR in a specific respiratory epithelial cell line.
The research team analyzed the association between STAT3 and survival among patients with CF who spanned 3 birth cohorts at a single center from 1959 to 1994. In addition, they treated 2 respiratory epithelial cell lines with STAT3 inhibitors to assess changes in CFTR expression.
“We queried the association of STAT3Sat alleles with patient survival in a large group of CF patients spanning several decades of birth years,” the authors wrote. “Furthermore, we directly interrogated the effect of STAT3 inhibition on CFTR expression in epithelial cell cultures to validate our previous findings on the association of reduced STAT3 transcript levels with improved CFTR function.”
The results showed that STAT3 positively affected survival by leading to increased CTFR function in the oldest patient cohorts (those born before 1976), but not in those who were born later. The authors found that the role of STAT3 in survival changed, as did symptomatic treatments for CF and the overall survival of these patients, suggesting that the treatment of patients born later appears to have eliminated the survival-enhancing influence of STAT3.
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The treatment of respiratory epithelial cell lines with STAT3 inhibitors revealed opposing effects of STAT3, such that it can promote epithelial differentiation, which is disadvantageous in CF, and that it can stimulate defense against infection, which is advantageous for these patients.
The authors recommend future studies to further investigate the association between patients’ STAT3 genotype and the immune cell phenotype, with the aim of better understanding the underlying mechanism of the effects of STAT3 on CTFR protein function and overall CF survival.
Dunsche I, Raddatz EL, Ismer H, et al. Analysis of cystic fibrosis patient survival confirms STAT3 as a CF modifying gene with changing impact over time. Hum Mol Genet. Published online September 1, 2022. doi:10.1093/hmg/ddac221