RAGE And Its Genetic Polymorphism In Lung Cancer

Background:Lung cancer is the most common malignancy and the leading cause of cancer--associated mortality worldwide.Though its incidence and mortality in developed countries are declining,in developing countries,especially in China,they are still on the rise due to environmental pollution and smoking.So there is an imminent to deepen the understanding of the mechanism of lung cancer development and metastasis,screen their prognostic indicators,find new early diagnostic methods and therapeutic targets,and improve the effectiveness of individualized treatment.The receptor of advanced glycation end products(RAGE),a member of the immunoglobulin superfamily,is expressed at low levels in most adult tissues under normal physiological conditions,but high in normal lung tissues.During malignant transformation its expression is significantly reduced in lung again.By binding to.its ligands,RAGE participates in the proliferation,invasion and metastasis of tumors,and plays an important biological role in many malignant tumors.Several ligands have been identified for RAGE,including amyloid,advanced glycation end products,S100 calcium binding protein,high mobility group protein 1(amphoterin,HMGB1).The combination of RAGE with these ligands not only interferes with cell homeostasis under physiological conditions,but also affects cell migration and differentiation.Studies have suggested that overexpression of S100P is associated with poor prognosis in lung cancer.Increased expression of HMGB1 in immature cells and tumor cells plays an important role in tumor invasion and metastasis,so interfering RAGE and itsligands or their interaction may be a target for lung cancer treatment.Soluble RAGE(sRAGE),the extracellular domain of RAGE,which has a ligand binding site,is widely distributed in extracellular fluid and can inhibit the RAGE-mediated pathological effects.It has been suggested that the different levels of sRAGE in gastrointestinal neoplasms and breast cancers are associated with the pathological type and prognosis of the tumor.A small number of studies have also reported that high expression of HMGB1 and low expression of RAGE in lung cancer tissues and low level of sRAGE in peripheral blood can be used as a new biomarker of lung cancer.The occurrence of lung cancer is mainly related to environmental carcinogens,but the genetic background is also an important factor in determining the prognosis of individual lung cancer susceptibility and tumor differentiation,invasion and metastasis.Therefore,tumor gene polymorphism has always been a hot topic.In the Chinese population,RAGE's Gly82Ser gene polymorphism increased the risk of gastric cancer,and there are also significant changes in the RAGE gene promoter polymorphism in NSCLC.In breast cancer and pancreatic cancer patients,no changes of alleles and gene sequences in RAGE gene polymorphism,but the increasingof sRAGE levels have relationship with themwere found.Purpose:At present,there are few studies focusing on the correlation between RAGE,sRAGE and its ligands and lung cancer typing,staging and smoking.Therefore,this study was designed to explore the correlation between RAGE and itsligands,sRAGE and RAGE gene polymorphismsin invasion and metastasis of lung cancer,and to provide theoretical basis for further target therapy.Materials and Methods:1.275 patients with lung cancer and 126 healthy controls were selected.Peripheral blood was collected from all the subjects.The serum was collected and the whole blood DNA was extracted.And we selected 50 post-operation lung cancer tissues and the adjacent normal tissues paraffin blocks(squamous cell lung cancer 25,adenocarcinoma 25)for immunohistochemistry test.2.The levels of serum sRAGE in lung cancer and healthy control group were detected by ELISA.The expression of RAGE and its ligands in lung cancer tissues and adjacent tissues were measured by immunohistochemistry.3.The polymorphisms of RAGE genotype-429 T/C,-374 T/A,Gly82Ser and 2184A/G were detected by polymerase chain reaction-restriction fragment length polymorphism(PCR-RLFP).Results:1.Compared with the healthy control group,the serum sRAGE level of patients with lung cancer decreased,the difference was statistically significant.Meanwhile,the levels of sRAGE in smokers with lung cancer were lower than those of non-smokers,2.Compared with the adjacent tissues,the expression of RAGE was decreased in the lung cancer tissues,while the expression of RAGE ligands(including HMGB1 and S100)increased.3.Polymorphism study showed that the frequency of TT allele and T allele in patients with lungsquamous cell carcinoma was significantly lower than that in control group(P=0.047).In lung adenocarcinoma,andsquamous cell carcinoma.,there were also significant differences of the polymorphism of 2184A/G in the early-middle and late stages.Conclusion:RAGE and sRAGE may be the biomarkers for lung cancer diagnosis and prognosis.RAGE polymorphism genotype-429T/C and 2148A/G are related to the occurrence and progression of lung cancer.