Pathological Role Of Menin In Mediating Radiation-induced Lung Injury Through Epithelial Mesenchymal Transition

Radiation-induced lung injury,the most common complication of chest radiotherapy.Studies have shown that the formation of radiation-induced lung injury undergoes epithelial mesenchymal transition(EMT).Nowadays the survival rate of lung cancer patients is increasing,and radiation-induced lung injury has also gathered attention a lot.The nuclear protein menin which is encoded by gene MEN],and interaction with histone modification enzymes such as mixed lineage lymphoma gene(MLL)to regulate key target genes and participating in the regulation of various cell phenotypes.Studies have shown that in breast cancer cells,menin interacts with RPA2 to promote cell proliferation,adhesion,metastasis,invasion and occur of EMT.It gives a clue that menin has potential biological function in the EMT process.In the pre-laboratory study,Kras mutation induced EMT in the process of lung adenocarcinoma,and MEN1 gene deletion inhibited the EMT process induced by Kras mutation.This suggests that menin is involved in the regulation of lung cancer EMT.However,the mechanism of action of menin in the EMT process caused by radiotherapy is still unclear.Therefore,this study sought to explore the role of menin in radiation-induced lung EMT and to investigate whether menin mediates the progression of radiation-induced lung injury via EMT.Based on the above scientific problems,animal models of radiation-induced lung injury were divided into wild type group,the Menl single gene knockout group,the single irradiation group and the Men]gene knockout combine irradiation group.The lung tissues of the mice were collected 8 weeks and 16 weeks after the irradiation respectively.Via immunohistochemistry experiments,It indicated that radioactive pneumonia occurred 8 weeks after irradiation,which showed that it was the inflammatory phase of radiation-induced lung injury during 8 weeks of irradiation.Masson staining experiment showed radioactive pulmonary fibrosis occurred after 16 weeks of radiation,indicating that the status was in the fibrosis stage of radiation-induced lung injury at 16 weeks of irradiation.By way of HE staining and immunohistochemistry experiments,it was found that the EMT process accelerated after knockout of Men1 gene,and mice's lung inflammation increased.The 2 results indicated that Men1 deficiency accelerated the process of radiation pneumonitis.Through the Masson staining and immunohistochemistry experiments,it was found that the EMT process accelerated and the lung fibrosis of reaction increased in mice after knockout of the Men1 gene.These indicated that the Men1 deficiency accelerated the process of radioactive fibrosis.Since the menin-MLL interaction involved in various biological functions,it would be investigated that whether acceleration of radiation-induced lung injury caused by knockout of menin is related to MLL.It was found that EMT levels were significantly inhibited after MLL single gene knockout.It indicated that both menin and MLL are involved in the EMT process caused by radiation,but the mechanism of actions were not necessarily same.In summary,menin plays a key inhibitory role in the process of radiation-induced lung injury.This study provides new insights into the prevention and treatment of lung injury caused by radiotherapy.