Clinicopathological Significance Of Expressed NF-?B,TLR4,p-Stat3 And Survivin In Gastric Cancer And The Impacts On Disease Prognosis

Objective: To investigate the expressions of NF-?B,TLR4,Survivin and the activation of Stat3(p-Stat3)in tissues of patients with gastric cancer(GC)and their adjacent non-cancerous tissues(ANT)by immunohistochemistry in order to explore the correlations of Stat3 signaling pathway and its related molecules with GC patients' clinicopathological parameters and survival prognosis.Methods:(1)Tissues from 118 gastric cancer cases and their 75 adjacent non-cancerous(ANT)tissues were collected from the First Affiliated Hospital of Shihezi University School of Medicine from 2008-2013.All the 118 patients with gastric cancer(GC)had complete pathological data and follow-up information,and informed consent was obtained.(2)Until October 2015,118 patients with GC were followed up every year.The longest follow-up time of these patients was over 7 years.(3)Tissue microarrays were made from paraffin embedded tissue blocks.The expression of NF-?B,TLR4,p-Stat3 and Survivin was detected by immunohistochemical assay(IHC)using these microarray chips.IHC data was analyzed using non-parametric method,Spearman correlation analysis,Kaplan-Meier survival analysis,Cox regression analysis included in SPSS 20.0 software package.Results:(1)GC tissues had a positive expression ratio of 50.9% for NF-?B(60/118),which was higher than ANT tissues with a ratio of 16%(12/75).The TLR4 positive expression ratio in GC tissues was 59.1%(68/115),higher than the ANT tissues positive expression ratio of 15%(11/75).The active p-Stat3 in GC tissues was detected to be 58.7%(57/97),much higher than that in ANT tissues of 7.7%(5/65).The Survivin positive expression ratio in GC tissues is 87.1%(81/93),which is higher than the ANT tissues expression ratio 5.0%(3/59).(2)In GC,the NF-?B expression is correlated with the invasion depth(P=0.008),distant metastasis(P=0.007)and clinical staging(P=0.006),however,it is not correlated with sex(P=0.99),age(P=0.79),WHO classification(P=0.49)and lympho node metastasis(P=0.21);the TLR4 expression is not correlated with Clinical pathological indicators;the p-Stat3 expression is correlated with the WHO classification(P=0.02),lympho node metastasis(P=0.05),distant metastasis(P=0.02)and clinical staging(P=0.03),however,it is not correlated with sex(P=0.68),age(P=0.86),invasion depth(P=0.35);the Survivin expression is not correlated with Clinical pathological indicators.(3)Till the October,in 2015,52.4%(64/118)gastric cancer patients were still alive,whereas 45.8%(54/118)had died.Follow-up ranged from 0 to 89 months and the median survival time was 34.5 months.The survival analysis reveal the expression of NF-?B,TLR4,p-Stat3 and Survivin correlated with the survival prognosis in GC.The ROC curve predicts that the area under the line of NF-?B,TLR4,p-Stat3 and Survivin are 0.86,0.70,0.71 and 0.65,respectively.(4)After analyzing the correlation between clinical pathological parameters and NF-?B,TLR4,p-Stat3,and Survivin,we found that there is a positive correlation between(differentiation,lymph node metastasis,distant metastasis,and TNM staging)and p-Stat3 and(distant metastasis,and TNM staging)and NF-?B.After analyzing the correlation between NF-?B,TLR4,p-Stat3 and Survivin,we found that NF-?B is positively correlated with TLR4 and Survivin,as well as positive correlation between TLR4 and Survivin.(5)Cox single factor regression analysis showed that differentiation,depth of invasion,lymph node metastasis,distant metastasis,TNM stage,NF-?B,TLR4 and p-Stat3 were prognostic factors for GC patients.Multivariate regression analysis,however,suggested that NF-?B and p-Stat3 were independent prognostic factors for GC patients.Conclusions:(1)The expression of NF-?B,TLR4,p-Stat3 and Survivin in GC tissues is higher than ANT tissues,suggesting that the expressed NF-?B,TLR4,p-Stat3 and Survivin may be associated with the development of GC.(2)The highly expressed NF-?B in GC tissues are correlated with distant metastasis and TNM stages;highly activated p-Stat3 correlate with GC patients characterized with low differentiation,lymph node metastasis,distant metastasis and TNM stages;and NF-?B also shows a positively correlation with p-Stat3,suggesting that both NF-?B and p-Stat3 may be coordinately involved in the development and progression of GC.(3)The correlation of increased levels of NF-?B,TLR4,p-Stat3 and Survivin with poor patient prognosis suggest that these molecules and their related signaling pathway have clinical significance of predicting survival prognosis for patients with gastric cancer.