Expression Of TNFR2 In Human Non-small Cell Lung Cancer And Its Role As A Potential Prognostic Biomarker

Background: Lung cancer is the most common malignant tumor with the highest morbidity and mortality worldwide.It is estimated that about 154,050 people will die of the disease in 2018 worldwide.Notably,human non-small cell lung cancer(NSCLC)accounts for about 85% of all primary lung cancers.With the recent development of tumor immunotherapy,molecular pathways underlying NSCLC progression have been explored and targeted drugs have brought new hope to some patients with NSCLC.However,the 5-year survival rate(approximately 18%)is still very low.Therefore,it is necessary to identify new and more effective therapeutic targets for NSCLC.Both TNFR1 and TNFR2 are receptors of TNF.These two receptors trigger divergent signaling pathways upon interactions with TNF due to their different cytoplasmic domains.TNFR1 signaling pathways have been extensively characterized.However,compared to TNFR1,few TNFR2 signaling pathways have been elucidated.Reports of TNFR2 functions in tumor progression have recently increased.TNFR2 has been found in various cancers.TNFR2 is considered a tumor-promoting factor and participates in tumor progression by promoting tumor cell proliferation,activating immunosuppressive cells,and supporting immune escape.Hence,TNFR2 may represent a potential target for cancer therapy.Objective :To investigate the expression of TNFR2 in human NSCLC tissues and cell lines,to explore the correlation between the expression of TNFR2 and clinical parameters of NSCLC patients and the survival of patients with NSCLC,it may provide a new therapeutic target for the treatment of patients with NSCLC;Moreover,it may enrich the study on the molecular biological mechanisms of TNFR2 and provide a strong evidence for the development of NSCLC new therapeutic targets.Method: TNFR2 was evaluated by quantitative real-time PCR and western blotting in three NSCLC cell lines,A549,H1299,H1975,and the normal lung epithelial cells BEAS-2B.TNFR2 was evaluated in 71 tumor tissues and 25 adjacent normal lung tissues by immunohistochemistry and analyzed with respect to clinical parameters.Results: The mRNA and protein levels of TNFR2 were significantly higher in A549,H1299,and H1975 cells than in BEAS-2B cells(P < 0.05)and differed significantly between NSCLC tissues and adjacent normal lung tissues by IHC(P < 0.0001).High TNFR2 expression was associated with tumor stage(P = 0.006)and lymph node metastasis(P = 0.012).Based on TNFR2 expression,71 NSCLC specimens were divided into 2 groups,a low expression group(n = 46)and and a high expression group(n = 25).8 of 46 patients in the low TNFR2 group were classified as stage III/IV,which was significantly lower than the proportion in the high expression group,12 of 25 patients(P = 0.006).A total of 12 of 46 patients in the low TNFR2 group had lymph node metastasis,which was significantly lower than the proportion in the high TNFR2 group,14 of 25 patients(P = 0.012).However,differences in age,gender,and tumor size between the two groups were not significant.These results confirm the associations of TNFR2 with clinical stage and lymph node metastasis.TNFR2 was correlated with shorter overall survival(OS)and disease-free survival(DFS)times.Univariate analysis showed that TNFR2(P = 0.022),clinical stage(P = 0.000),and lymph node metastasis(P = 0.000)were significantly related to OS.TNFR2(P = 0.002),clinical stage(P = 0.000),and lymph node metastasis(P =0.000)showed significant effects on DFS.Multivariate analysis showed that TNFR2(P = 0.036),clinical stage(P = 0.000),lymph node metastasis(P = 0.000),and adenocarcinoma subtype(P = 0.039)were significantly related to OS,and TNFR2expression(P = 0.002)and clinical stage(P = 0.000)were related to DFS.Conclusions1.TNFR2 is significantly expressed in human NSCLC tissues and cell lines.2.TNFR2 is associated with a poor prognosis of NSCLC and is expected to be a new prognostic indicator for patients with NSCLC.