Study Of The Effects And Regulatory Mechanisms Of Aldehyde Dehydrogenase 2 Family And Sperm-associated Antigen 5 On Lung Adenocarcinoma

Lung cancer is the leading cause of cancer-related death in the world.The progression of lung cancer has been linked to increased genomic instability,which could be induced by various factors including cigarette smoking,reactive oxygen species(ROS)and cytotoxic metabolites.ALDH2 is mainly responsible for detoxification of acetaldehyde(ACE)to non-toxic acetic acid.Many studies suggest that ALDH2 dysfunction is associated to a variety of human diseases including cancer.However,the biological function and regulatory mechanism of ALDH2 and its metabolite ACE in lung cancer remain unclear.Define the function and regulatory mechanisms of ALDH2 in lung cancer will provide theoretical basis for the development of new strategies for cancer therapy.In this paper,we found that ALDH2 was down-regulated in lung adenocarcinoma and the repression of ALDH2 is related to poor prognosis in patients with lung adenocarcinoma.Cell biology experiments showed that the overexpression of ALDH2 inhibited malignant features of lung adenocarcinoma cells,such as proliferation,stemness and migration.Mechanistically,ALDH2 repression leads to accumulation of ACE and ACE enhances the migration features of lung adenocarcinoma cells via increasing DNA damage.Furthermore,the treatment of Alda-1,the ALDH2 agonist on lung adenocarcinoma cells suppressed the stemness and metastatic features of lung adenocarcinoma cells.In conclusion,ALDH2 repression promotes lung adenocarcinoma progression and the regulation to migration capacity depends on accumulated ACE and increased DNA damage,so targeting ALDH2 such as via its agonist may provide a novel strategy for lung cancer therapy.Lung cancer cells often present uncontrolled division and proliferation.Cell division and cell cycle-associated regulatory proteins play crucial roles in the progression of lung cancer.Sperm-associated antigen 5(SPAG5,also known as Astrin and hMAP126)is a mitotic spindle-associated protein,which is abnormally expressed in a variety of tumors,leading to activation of some oncogenic pathways.However,the study about the function of SPAG5 on lung adenocarcinoma is limited and the regulatory mechanism of SPAG5 is also unclear.In our study,we found that SPAG5 was highly expressed in lung adenocarcinoma and the upregulated SPAG5 was associated to poor prognosis in lung adenocarcinoma patients.We also showed that the administration of the Mouse double minute 2 homolog(MDM2)inhibitor,Nutlin-3a,inhibited the expression of SPAG5 by regulating the p53 signaling pathway in lung adenocarcinoma cells.In summary,SPAG5 is a poor prognostic marker and potential therapeutic target of lung adenocarcinoma.The therapeutic strategy targeting the p53-p21-SPAG5 axis may have important clinical implications.