The polymorphisms of IL-6/STAT3 signaling pathway may contribute to cutaneous T-cell lymphomas susceptibility

Abstract

IL-6/STAT3 signaling pathway has been suggested to play a role in CTCL pathogenesis. Polymorphisms in STAT3 signaling pathway-related genes might be a risk factor for CTCL. However, the exact role of inherited gene polymorphisms of IL-6 and STAT3 in the pathogenesis of CTCL is still not fully understood. The aim was to examine whether IL-6 cytokine and polymorphisms of IL-6 and STAT3 gene are associated with CTCL susceptibility, stage of disease and pruritus intensity. We compared the IL-6 serum level and the frequency of selected single nucleotide polymorphisms of IL-6 and STAT3 in 106 CTCL and 198 control group using polymerase chain reaction with sequence-specific primers method and ELISA. We have found that serum IL-6 level in CTCL patients was significantly higher than in healthy controls (p < 0.05). We also demonstrated that two genotypes, CC of IL-6 and GG of STAT3, were overexpressed in CTCL patients compared to healthy controls, and that they increase the risk of malignancy development (OR = 1.8, p = 0.04 for IL-6 and OR 2.53, p = 0.0064 for STAT3). Moreover, the GG genotype of STAT3 polymorphism seems to be associated with lack of pruritus or mild pruritus in CTCL patients. Our results indicate that IL-6 is involved in pathogenesis of CTCL but not pruritus. Moreover, CC of IL-6 and GG genotype of STAT3 genes might be considered as the risk factor for development of CTCL.

SnapshotDx Quiz: January 2022

“…In the skin, STAT3-deficient mice have compromised hair cycles and wound healing that is thought to be secondary to deficient migration of keratinocytes (Levy and Lee, 2002). Interestingly, a recent observational study examining serum levels of IL-6 between patients with CTCL and healthy controls identified IL-6 polymorphisms linked with CTCL susceptibility (Olszewska et al, 2021). Furthermore, Olszewska et al (2021) found that a particular STAT3 genotype correlated with decreased pruritus intensity in the CTCL cohort.…”

“…Interestingly, a recent observational study examining serum levels of IL-6 between patients with CTCL and healthy controls identified IL-6 polymorphisms linked with CTCL susceptibility (Olszewska et al, 2021). Furthermore, Olszewska et al (2021) found that a particular STAT3 genotype correlated with decreased pruritus intensity in the CTCL cohort. Nevertheless, Cortes et al (2021) did not identify IL-6/STAT3 signaling as a mediator of romidepsin and mechlorethamine synergism but rather a reduction in phosphorylated STAT5 (Figure 4a) (Cortes et al, 2021).…”

Targeted Approaches to T-Cell Lymphoma

“…Aberrancies in the JAK/STAT pathway are common in T-cell lymphomas, with one series reporting an association with worse outcomes in PTCL [60]. The JAK/STAT pathway is also a potential mediator of pruritus in CTCL [61]. The tyrosine kinase Syk is a driver of cellular growth and survival in healthy and malignant B-cells and not usually expressed on normal T-cells.…”

Epigenetics in the Pathogenesis and Treatment of Cutaneous T-Cell Lymphoma

“…STAT3 is also frequently dysregulated in CTCL ( 112 ). STAT3 activation plays a role in CTCL pathogenesis ( 125 ) and progression ( 126 ) and large-cell transformations ( 127 ) MiRNAs, such as miR-337 ( 123 ) and miR-124 ( 128 ), mediate the expression of STAT3. In particular, miR-124 silencing caused by the hypermethylation of the miR-124 promoter region was shown to increase STAT3 levels in CTCL.…”