The Role And Mechanism Of Destrin In The Initiation And Development Of Lung Adenocarcinoma

Background:Lung cancer is one of the malignant tumors with high morbidity and mortality in the world,of which lung adenocarcinoma accounts for 40-50%.In recent years,the incidence of lung cancer in our country has been on the rise and has now become the primary cause of cancer death in urban areas in China.In the population,there are some difficulties in the early detection of lung cancer patients.Most of the lung cancer patients who are clinically treated are in the advanced stage.Therefore,the screening of early biomarkers of lung cancer and the role,mechanism and application of important biomarkers in the development of lung cancer are important for the early diagnosis,the treatment and prognostic evaluation of the disease.Destrin(actin depolymerization factor)is one of the important members of the ADF/cofilins family.It participates in the regulation of various cellular processes and plays an important role in the assembly of cell actin filaments.Studies have shown that Destrin is involved in the growth,infiltration,and metastasis of many kinds of tumors such as pancreatic cancer,breast cancer,and colorectal cancer;during the iTRAQ quantitative proteomics high-throughput screening of mouse lung cancer model we found that Destrin was significantly higher expression in lung tissue of lung cancer group than the control group,and it was higher in liver metastasis mice.However,the relevant mechanism and significance have not been reported at present.Objective:To explore the role of Destrin in the development,progression and metastasis of lung adenocarcinoma and related mechanisms.Methods:A mouse model of lung cancer was established by intraperitoneal injection of Urethane(850mg/kg).The serum,lung and liver tissues of experimental group and control group were taken at different time points of 16,20,24,28 and 32 weeks after model establishment.Differential proteomic analysis of lung tissue samples 16 weeks after modeling was performed using iTRAQ technology.According to bioinformatics analysis and literature review,the major differential protein Destrin was selected for immunohistochemistry and Western blot analysis.Using clinical lung adenocarcinoma tissue samples andfollow-up data to explore the significance of Destrin in lung cancer diagnosis and prognosis evaluation.The lung adenocarcinoma cell line A549 was used to investigate the possible mechanisms of Destrin and tumor growth,invasion and metastasis through RNAi,immunofluorescence and other cell biology and molecular biology methods.Results:Quantitative iTRAQ analysis found that the expression level of Destrin in early lung adenocarcinoma tissue was 3.6 times higher than that in the control group.Immunohistochemistry and Western blot validation analysis showed that the expression level of Destrulin increased with the development of lung cancer in mice,and the increase of Destrin was more evident in the rats with liver metastasis.Immunohistochemical analysis of clinical lung adenocarcinoma specimens also showed high expression of Destrin,and the expression level of Desrin was closely related to the pathological stage and lymph node metastasis of lung adenocarcinoma.Cox proportional hazards model and survival analysis showed that Destrin can be used as an independent risk factor for the survival of lung cancer patients,and its expression level affects the prognosis of patients.Using shRNA technology to knockdown Destrin in A549 cells,it was found that the morphology,adhesion,proliferation,and metastasis of Destrin-silenced A549 cells were all changed,E-cadherin and vinculin were up-regulated,and β-catenin localization was changed,and Destrin silence resulted in A549 cells Apoptosis sensitivity to cisplatin increased,tumor bearing experiments in nude mice did not show tumor growth in the silent group.Conclusions:Destrin is an important protein in the process of lung carcinogenesis.Its abnormal expression may play an important role in the occurrence,development,metastasis and prognosis of lung adenocarcinoma.It may be one of biomarkers for early diagnosis and prognosis evaluation of lung adenocarcinoma.