Diabetes Affects The Growth And Metastasis Mechanism Of Lung Cancer Through RAGE-NOX4 Pathway

Objective:Studies have shown that for patients with advanced lung Cancer,diabetes mellitus has an adverse effect on the prognosis.However,it is still unknown whether diabetes mellitus will affect tumor growth and metastasis in patients with early and middle stage lung Cancer,especially those with surgically resectable lung Cancer.This paper aims to study the adverse effect of diabetes mellitus on the prognosis of patients with non-small Cell lung Cancer(NSCLC).Methods:We collected a sample including 857 patients who had Non-Small Cell Lung Cancer and underwent lung cancer resection in our hospital from the year 2016 to 2019.For experiment data,we recorded the age of admission,gender,preoperative blood glucose,medical records and some general conditions such as serious cardiovascular and cerebrovascular diseases of all 857 patients.Besides,data such as Overall Survival(OS)were obtained through regular follow-up.According to the preoperative blood glucose level,these patients were divided into high glucose group(HG,blood glucose level value was higher than or equal to 8)and normal glucose group(NG,blood glucose level value was lower than or equal to 6).Furthermore,in order to explore the influence of blood glucose level on patients' long-term prognosis and possible mechanism of the influence,we analyzed the difference of patient's total survival time,the maximum diameter of the tumor and the condition of lymph node metastasis between the high blood glucose group and normal blood glucose group.Results:We compared the difference of average survival rate,long-term survival rate,the maximum diameter of tumor and the condition of lymph node metastasis of patients in the high blood glucose group and those in the normal blood glucose group.As a result,we found that the average survival rate and the long-term survival rate of patients in the high blood glucose group were significantly lower than the patients in the normal blood glucose group.As for the maximum diameter of tumor,the average diameter value of the patients in the high glucose group(4.45 cm)was larger than the patients in the normal blood glucosegroup(3.47cm).For the condition of lymph node staging,the proportion of N2 and N3 in the high blood glucose group(50%)was higher than that in the normal blood glucose group(32.13%),the difference was significant with the P value less than 0.05.Conclusion:According to our study,high blood glucose can decrease the long-term survival of patients with lung cancer in patients with diabetes by promoting tumor growth and lymph node metastasisObjective:In the past decades,studies have shown that increased blood glucose can promote the growth of lung cancer cells,but it is still not clear how blood glucose affects the growth of lung cancer cells.We hope to provide a new idea for the study of the mechanism of diabetes on lung cancer through our study.Methods:In this study,A549 lung adenocarcinoma cell lines were cultured in DMEM medium containing high concentration of glucose(25mmol/L)and ordinary concentration of glucose(5.5mmol/L),respectively.After 24 hours,the proliferation ability of each experimental group was tested by MTT colorimetry,the proliferation ability was tested by wound healing test,and the related proteins in RAGE-NOX4 pathway were quantitatively and quantitatively analyzed by fluorescence quantitative PCR and protein western blot test,so as to determine its potential role in tumorigenesis related to glucose metabolism.Results:The present study demonstrated that HG could increase the protein expression of RAGE and NOX-4,whereas the inhibitor of RAGE(anti-RAGE antibody)could suppress this effect.Futhermore,the inhibitor of NOX [diphenyl iodonium chloride(DPI)] could reduce the protein expression of RAGE and NOX-4.Furthermore,inhibition of RAGE led to the downregulation of vascular endothelial growth factor(VEGF)and hypoxia-inducible factor-1?(HIF-1?),thus suggesting that HG may influence angiogenesis and tumor metabolism via the RAGE-NOXs pathway.The present study also demonstrated that the RAGE-blocking antibody downregulated NOX-4 and subsequently reduced the production of downstream inflammatory factors,whereas DPI did not affect the m RNA expression of RAGE but it did reduce the protein level of RAGE and then attenuate the inflammatory response.Conclusion:These results indicated that inhibition of RAGE or NOXs may promote the reduced expression of VEGF and HIF-1?,and NOXs may be downstream targets of RAGE,thus indicating a HG-RAGE-NOXs-VEGF/HIF-1? association.Furthermore,the results indicated that HG may serve a role in the development of lung adenocarcinoma,mediated by the RAGE-oxidative stress pathway;therefore,the regulation of this glucose-associated pathway may be a promising novel direction for oncotherapy.In addition,through the follow-up and analysis of clinical cases,this study found that diabetes can affect the prognosis of patients by promoting tumor growth and lymph node metastasis,and then reduce the long-term survival rate of patients with diabetes complicated with lung cancer.This is consistent with our previous studies,demonstrating the importance of glycemic control in patients with this type of lung cancer.However,while certain antidiabetic agents have been verified to exert inhibitory effects on tumor growth,they can also have long-term adverse effects on the body,which may limit the value of these drugs as anticancer treatments.In conclusion,the present study suggested a novel attempt to suppress glucose-induced tumor growth using a RAGE inhibitor such as soluble RAGE while avoiding the risk of glucose fluctuation.