STAT3 Cooperates With AR/CCRK Signaling Pathway In The Progression Of Chronic HBV Infection And Gender Differences

STAT3 cooperates with AR/CCRK signaling pathway in the progression of chronic HBV infection and gender differencesPart one STAT3 cooperates with AR/CCRK signaling pathway in the progression of chronic HBV infection and gender differencesAims:To investigate the role of AR/CCRK signaling pathway in chronic hepatitis B virus(HBV)infection and gender differences,and the contribution of AR regulatory factor STAT3 in it,to evaluate STAT3 and AR as combined therapeutic targets for the prevention of chronic HBV infection progression.Methods:AR,CCRK,and phosphorylated STAT3 expressions in liver tissues of chronic HBV-infected patients and non-HBV controls were determined by western blot and compared between genders.The relationships of expression levels with serum HBV DNA levels,liver inflammation activity and fibrosis score were analyzed in chronic HBV-infected patients.The relationships between expression levels of three proteins were also analyzed.Results:HBV-infected patients had significantly higher expression levels of AR,CCRK,and p-STAT3Tyr705 compared with controls(P<0.01).The expression levels of AR,CCRK,and p-STAT3Tyr705 in chronic HBV-infected patients with severe inflammation were significantly higher than those with mild inflammation(P<0.05).Expression levels in patients with heavier fibrosis(stage F4)were higher than those with less fibrosis(stage F0-3)(P<0.01).No gender differences were observed in AR,CCRK and p-STAT3Tyr705 levels in non-HBV controls;higher levels were observed in HBV-infected males than in HBV-infected females(P<0.05).AR,CCRK,and pSTAT3Tyr705 levels in liver tissues positively correlated with each other(r=0.5991,0.5349,and 0.7548,respectively;P<0.0001)and with serum HBV DNA levels(r=0.6625,0.7368 and 0.6349,respectively;P<0.0001).Conclusion:In this study,we found concordant over-expression of AR,CCRK and STAT3 in liver tissues of chronic HBV-infected patients,significantly correlated with the severity of the disease and showed gender differences.STAT3 cooperating with the AR/CCRK signaling pathway affects the development and gender differences of chronic HBV infection.Part two STAT3 rs744166 SNP affects AR/CCRK pathway protein expression,and is related to the fibrosis process of male chronic HBV infectionObjective:To explore the relationship between STAT3 polymorphism and the progression of fibrosis in chronic HBV infection and the expression of AR/CCRK pathway protein,so as to find out the potential host genetic factors affecting fibrosis progression in chronic HBV infection,and to explore the internal mechanism of its role,thus providing a theoretical basis for its clinical application.Methods:The gene polymorphisms of STAT3 rs2293152,rs1053005,rs1053004,and rs744166 were analyzed by gene sequencing.The distribution of different genotypes in different fibrosis stages of chronic HBV infection was observed.At the same time,the expression levels of STAT3,AR and CCRK in liver tissues of patients with different genotypes were compared to explore their correlation.Finally,multivariate logistic regression analysis was used to screen the independent factors related to fibrosis progression.Results:The genotype distribution of STAT3 rs744166 were different in patients with chronic HBV infection at different stages of fibrosis.Compared with patients with early liver fibrosis,patients with advanced liver fibrosis had a significantly lower proportion of G(GG+AG)genotype at rs744166,especially AG positive patients(OR=0.453 and 0.368,P=0.006 and 0.001,respectively).There was no significant difference in the distribution of rs2293152,rs1053005 and rs1053004 genotype between early and advanced liver fibrosis.Stratified by sex,it was found that the influence of STAT3 rs744166 genotype on fibrosis progression in patients with chronic HBV infection was different in different genders.The genotype distribution of rs744166 locus was different in men with different degrees of liver fibrosis(P=0.019).Compared with patients with early liver fibrosis,the proportion of G(GG+AG),especially AG,was significantly lower in patients with advanced liver fibrosis(P=0.016 and 0.006,respectively).However,there was no significant difference in genotype distribution among women with different degrees of fibrosis(P>0.05).The relationship between STAT3 genotype and the expression of AR pathway protein in liver tissues was analyzed.The results showed that the expression levels of STAT3,AR and CCRK in patients with rs744166 G(GG+AG)were significantly lower than those in patients with AA(P<0.05).Logistic regression analysis showed that male(OR=2.365,P=0.013),age ≥ 50 years old(OR=4.950,P<0.001),smoking(OR=2.014,P=0.029)and rs744166 G(GG+AG)type(OR=0.496,P=0.027)were independent influencing factors for the occurrence of advanced liver fibrosis.After stratification according to gender,the results showed that in male patients,age≥50 years old(OR=5.183,P<0.001),HBeAg positive(OR=0.366,P=0.007)and rs744166 G(GG+AG)type(OR=0.178,P=0.043)were independent factors affecting the progress of liver fibrosis.In female patients,age≥50 years(OR=4.824,P=0.009)was an independent influencing factor for the progression of liver fibrosis.Conclusion:STAT3 rs744166 polymorphism is associated with the expression level of STAT3 and AR pathway proteins,and affects the progression of liver fibrosis in chronic HBV infection,especially in male patients.It can be used as an independent predictor of liver fibrosis progression in chronic HBV infection.