Relationship And Pathogenesis Between Inflammation Markers And Non-small Cell Lung Carcinogenesis

Background and objective: With the application of low dose spiral CT in lung cancer screening,more and more lung cancer patients were diagnosed in early stage.However,the false positive rate is very high for LDCT examination.More markers were still need to predict early stage lung cancer risk for the improving of the five-year survival rate of lung cancer patients.The aim of the present study was to investigate the relationship between circulating inflammatory makers and early stage lung cancer risk.Meanwile,we tried to find the potiential pathogenesis of inflammatory-related lung cancer.The present study also evaluated the role of traditional peripheral blood tumor markers in predicting the risk of lung cancer.Methods: The present study collected 228 peripheral blood samples of new non-small cell lung cancer patients who accepted surgical treatment in Shanghai Chest Hospital during September 2013 and March 2015.Control subjects were matched to lung cancer case patients on age(� 2 years),sex,smoking status and sample collecting time(� 3 months).Serum levels of 10 inflammation markers were measured using a Luminex bead-based assay.The expression levels of mi RNAs were detected by real-time fluorescent quantitative PCR.Effects of inflammation factors and recovery of mi R-125 b expression on cell proliferation were compared with CCK8 method.Cell apoptosis were evaluated by flow cytometry.The expressions of mi R-125 b in non-small cell lung cancer and adjacent tissues were detected by real-time fluorescent quantitative PCR.The present also retrospectively collected 200 NSCLC patients who harboring EGFR sensitive mutations and accepting EGFR-TKI therapy during September 2010 and February 2014.Results: The higher expression of carcinoembryonic antigen(CEA)predicts longer progression free survival time(PFS)(12.8m vs 8.7m,HR=0.56,95%CI: 0.40-0.78,P=0.00078)in EGFR sensitive mutation NSCLC patients treated with EGFR-TKI when using 20 ng/ml as the cutoff value.And non-adenocarcinoma patients have worse PFS(3.5 vs 11 m,HR=2.88,95%CI: 1.71-4.86,P < 0.0001)compared with adenocarcinoma patients when accepting EGFR-TKI therapy.However,the expression level of CEA was not found related with early stage lung cancer risk(OR=1.05,95% CI: 0.68-1.63,P=0.82).Four inflammation markers were found associated with early stage lung cancer risk,MDC/CCL22(OR=0.29,95% CI: 0.16-0.53;Ptrend=1.0�10-5)and BLC/CXCL13(OR=4.17,95% CI: 2.23-7.79;Ptrend=1.0�10-5)were still found significant after Bonferroni correction(Ptrends<0.005).Further subgroup analysis revealed that MDC/CCL22 and BLC/CXCL13 were significantly correlated with the risk of non-smoker NSCLC,stage I and stage IA NSCLC.It was also found that BLC/CXCL13 was significantly associated with the risk of sub-centimeter lung cancer.The risk of highest expression group was 2.90 times higher than the lowest expression group(95%CI: 1.03-8.17,Ptrend=0.037).The expression level BLC/CXCL13 was increased as the progression of early stage of lung cancer(adenocarcinoma in situ,minimally invasive andenocarcinoma and invasive carcinoma,P=0.046).The expression level of Mi R-125 b changed most after stimulated with inflammation factors in non-small cell lung cancer cell lines.Mi R-125 b inhibited inflammatory cytokines induced cell proliferation and promote the apoptosis in non-small cell lung cancer cell lines.We also found that the expression of mi R-125 b in non-small cell lung cancer was significantly lower than that in normal tissue(P < 0.0001).The results of Affymetrix gene expression microarray showed that IGF-1 signaling pathway were significantly activate after down-regulated the expression of mir-125 b.Conclusion: Carcinoembryonic antigen(CEA)could predict the efficacy of EGFR-TKI in the treatment of late stage NSCLC.However,there is no association between CEA level and early stage lung cancer risk.Inflammatory markers,MDC/CCL22 and BLC/CXCL13 could predict the risk of early stage lung cancer.The level of BLC/CXCL13 increased as the progression of lung cancer indicating that it may play an important role in the development of lung carcinogensis.Mir-125 b may play a tumor suppressor role by inhibiting IGF-1 signaling in inflammation associated lung cancer.