Mechanism Of DCUN1D1 Promoting Proliferation And Invasion Of Lung Squamous Cell Carcinoma In Ge Jiu Miners

Lung cancer is one of the most common malignant tumors in the world,with the highest incidence and mortality.Lung cancer mainly includes squamous cell carcinoma and adenocarcinoma.There are few treatments for lung squamous cell carcinoma,and there is a lack of targeted effective therapeutic drugs including targeted drugs,therefore,the prognosis is poor.Yunnan Gejiu is China's largest tin mine industry base,However,tin mine workers'lung cancer morbidity and mortality are more than 20 times of that the normal population,ranking the first in the world for lung cancer incidence.lung cancer of Gejiu miners has always been one of the research hotspots of lung cancer in the world[1]Interestingly,epidemiological studies suggest that radon and arsenic exposure are important risk factors for Gejiu miners'lung cancer.The pathological type was mainly squamous cell carcinoma(squamous cell carcinoma accounted for 71.2%,adenocarcinoma only accounted for 9%)[2-4],suggesting that Gejiu miners'lung cancer may have its special pathogenesis,which also makes the Gejiu miners' lung cancer to become a good human body model for studying carcinogenesis caused by chemical carcinogens.Unfortunately,the pathogenesis of lung cancer in old miners has not yet been elucidated.Therefore,it is of great significance to study the driving genes and pathogenesis of lung cancer in Gejiu miners.Exploration of the driving genes and pathogenesis of Gejiu miners'lung cancer will provide new intervention targets for the prevention and treatment of lung squamous cell carcinoma and chemical carcinogenesis such as arsenic compounds.This study screened out the gene DCUN1D1 highly expressed in lung metastasis of old miners by gene chip.Further exploration of the biological function of this gene in the proliferation,migration,invasion and apoptosis of lung squamous carcinoma cells was taken after immunohistochemical verification of the chip results.Finally,the mechanism was preliminarily explored by Western blotting experiment.Through this research,the following conclusions are drawn:Compared with its expression in lung squamous cell cancer tissues of Non-Gejiu miners,DCUN1D1 is highly expressed in the cancer tissues of Gejiu miners'lung cancer.As the patient's clinical stage becomes late(Phase I gradually becomes Phase ?),the positive expression rate of DCUN1D1 gradually increased.DCUN1D1 promotes proliferation,migration and invasion of Ge Jiu miners'lung squamous carcinoma cell and ATCC lung squamous carcinoma cell.DCUN1D1 has no effect on the apoptosis of lung squamous cell carcinoma cells.In cell proliferation,the expression of cell cycle inhibitors p15,p16,p21,p27 and p53 was up-regulated after inhibiting the expression of DCUN1D1;The expression of the cell cycle promoting factor Cyclin E1 is down-regulated,which leading to cell cycle arrest in G1 phase and inhibiting cell proliferation.From the perspective of epigenetic modification,DCUN1D1 is an E3 ligase of Neddylation that promotes the process of Neddylation.Inhibition of DCUN1D1 expression may result in a decrease in the Neddylation of p53,which lead to increased transcriptional activity of p53 and increased expression of p53 protein.P53 further up-regulates the expression of p21 that leads to cell cycle arrest in G1 phase,which eventually leads to a weakened cell proliferation.In cell migration and invasion,there was no change in EMT-related genes after DCUN1D1 inhibition,while matrix metalloproteinase-2(MMP-2)expression was down-regulated.Combined with the results reported in the literature and our results,it is shown that the inhibition of migration and invasion of lung squamous carcinoma cell after DCUN1D1 inhibition is directly related to the down-regulation of MMP-2,but not related to EMT.The previous research shows that DCUN1D1 acts as a transcription factor to directly regulate the expression of key molecule Gli1 in Hedgehog(HH)signaling pathway.Our research shows that the expression of Gli-1 was also decreased after inhibition of DCUNID1 expression.We conclude that DCUN1D1 is most likely to directly regulate the expression of Gli1,and play a biological role in promoting proliferation,invasion and metastasis through the HH signaling pathway.